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Blood Transfusion Guideline PDF
Blood Transfusion Guideline PDF
Guideline
INITIATIVE:
National Users Board Sanquin Blood Supply
ORGANISATION:
CBO
MANDATING ORGANISATIONS
Netherlands General Practitioners Association (NHG)
Netherlands Internists Association
Netherlands Orthopaedic Association
Netherlands Association of Anaesthesiology Employees
Netherlands Association of bioMedical Laboratory Employees
Netherlands Association for Anaesthesiology
Netherlands Association for Blood Transfusion
Netherlands Association for Cardiology
Netherlands Association for Surgery
Netherlands Association for Haematology
Netherlands Association for Intensive Care
Netherlands Association for Paediatric Medicine
Netherlands Association for Clinical Chemistry and Laboratory Medicine
Netherlands Association for Medical Microbiology
Netherlands Association for Obstetrics and Gynaecology
Netherlands Association for Thoracic Surgery
Transfusion Medicine in Academic Hospitals
Association of Haematology Laboratory Research
Nurses & Carers of the Netherlands
FINANCING:
This guideline was created with financial support from ZonMw as part of the
Evidence-Based Guideline Development (EBGD) programme.
Copyright CBO
CBO
PO Box 20064
3502 LB UTRECHT
Tel.: 030 284 39 20
E-mail: mwr@cbo.nl
Table of contents
COMPOSITION OF THE WORKING GROUP ......................................................................... 7
GENERAL INTRODUCTION .................................................................................................. 10
CHAPTER 2: BLOOD COMPONENTS: CHARACTERISTICS, INDICATIONS, LOGISTICS
AND ADMINISTRATION ......................................................................................................... 18
2.1
Characteristics and blood components ................................................................... 21
2.1.1
Blood components: characteristics, general ......................................................... 21
2.1.2
Erythrocytes1, characteristics ................................................................................ 21
2.1.3
Platelet characteristics........................................................................................... 23
2.1.4
Platelet hyperconcentrate...................................................................................... 27
2.1.5
Plasma, characteristics.......................................................................................... 27
2.1.6
Granulocytes, characteristics ................................................................................ 28
2.2
Indications for blood components ........................................................................... 29
2.2.1
Erythrocytes ........................................................................................................... 29
2.2.2
Platelets ................................................................................................................. 31
2.2.3
Plasma ................................................................................................................... 32
2.2.4
Indication for irradiated blood components1.......................................................... 33
2.2.5
Indication for CMV-safe and CMV (sero)-negative components .......................... 34
2.2.6
Indication for Parvo B19 safe components ........................................................... 35
2.2.7
Indication for washed cellular components and IgA deficient plasma .................. 36
2.2.8
Indication for granulocyte transfusions ................................................................. 37
2.3
Storage conditions, shelf-life and transport............................................................ 39
2.3.1
Introduction ............................................................................................................ 39
2.3.2
Storage conditions, shelf-life and transport of erythrocytes ................................. 40
2.3.3
Storage conditions, shelf-life and transport of platelets ........................................ 43
2.3.4
Storage conditions, shelf-life and transport of plasma.......................................... 44
2.3.5
Shelf-life of irradiated components........................................................................ 46
2.3.6
Shelf-life of CMV negative / Parvo B19 safe components .................................... 46
2.4
Nursing aspects .......................................................................................................... 47
2.4.1
Nursing aspects, general....................................................................................... 47
2.4.2
Nursing aspects; administration ............................................................................ 48
ADDENDUM ............................................................................................................................ 59
CHAPTER 3: LABORATORY ASPECTS .............................................................................. 60
3.1
Accessory conditions for processing of requests for blood and blood
components ............................................................................................................................ 60
3.2
Laboratory examinations ........................................................................................... 63
3.2.1
Blood group determination .................................................................................... 63
3.2.2
Rhesus D blood group determination ................................................................... 65
3.2.3
Actions in case of ABO blood group discrepancies .............................................. 67
3.3
Compatibility study in transfusion of erythrocytes ................................................ 70
3.3.1
Antibody screening ................................................................................................ 70
3.3.2
Compatibility study ................................................................................................ 71
3.3.3
Antibody Identification Study ................................................................................. 76
3.3.4
The use of serum or plasma in antibody screening and cross matches .............. 79
3.4
3.5
Release and transfer of blood components ............................................................ 81
3.5.1
Procedure for release and transfer of erythrocyte concentrate ............................ 81
3.6
Selection of erythrocyte concentrate ....................................................................... 83
3.6.1
Selection of ABO/RhD compatible units (standard notation RhD) ....................... 83
3.6.2
Selection of blood components for patients with irregular antibodies .................. 85
3.7
Selection of erythrocytes for specific patient categories ...................................... 87
3.7.1
Selection of cEK-compatible erythrocytes for women of childbearing age .......... 87
3.7.2
Selection of erythrocytes for patients with haemoglobinopathies (see also
Chapter 4)............................................................................................................................. 88
3.7.3
Selection of erythrocytes for patients with auto-immune haemolytic anaemia .... 90
3.7.4
Selection of erythrocytes for patients with myelodysplastic syndrome ................ 91
3.7.5
Selection of erythrocytes for surgical procedures with hypothermia in patients
with cold antibodies .............................................................................................................. 91
3.8
Release of platelet concentrates .............................................................................. 92
3.8.1
ABO compatibility of platelets................................................................................ 92
3.8.2
RhD compatible platelets ...................................................................................... 95
3.9
Release of plasma....................................................................................................... 96
General guidelines for giving erythrocyte transfusions for chronic anaemia .. 108
4.2
Production disorders ............................................................................................... 110
4.2.1
Essential nutrient deficiencies (iron, folic acid, vitamin B12) .............................. 110
4.2.2
Bone marrow insufficiency .................................................................................. 111
4.2.3
Anaemia with chronic renal insufficiency ............................................................ 113
4.2.4
Anaemia with chronic illness, excluding renal failure / malignancy .................... 113
4.2.5
Anaemia during pregnancy ................................................................................. 114
4.2.6
Bone marrow / stem cell transplants ................................................................... 115
4.3
2
4.3.1
4.3.2
4.3.3
4.3.4
4.3.5
4.3.6
4.4
Breakdown disorders ............................................................................................... 125
4.4.1
Congenital: Sickle cell disease ............................................................................ 125
4.4.2
Elective indications for blood transfusion in patients with sickle cell disease .... 129
4.4.3
Congenital breakdown disorder: homozygous beta thalassaemia ..................... 135
4.4.4
Breakdown disorder: paroxysmal nocturnal haemoglobinuria (PNH) ................ 136
4.4.5
Breakdown disorder: Auto-Immune Haemolytic Anaemia (AIHA) ...................... 138
4.4.6
Haemolytic disease of the foetus and the newborn ............................................ 141
4.5
Anaemia in neonates* .............................................................................................. 146
4.5.1
Explanation of component choice for neonates .................................................. 147
4.5.2
Transfusion triggers in neonates ......................................................................... 147
4.5.3
Dosage of erythrocytes, administration and component choice ......................... 149
4.6
4.7
5.4.9
9.4.4
Use and implementation of indicators ................................................................. 386
9.4.5
Elaboration of indicators in fact sheets ............................................................... 387
Indicator 1. Blood Transfusion Committee ........................................................................ 387
Indicator 2. Haemovigilance employee .............................................................................. 389
Indicator 3. Operationalisation: laboratory information system. ........................................ 391
Indicator 4. Electronic pre-transfusion identification check ............................................... 392
Indicator 5. Indication setting for erythrocyte transfusions ................................................ 393
Indicator 6. Indication setting and measuring the effect of platelet transfusions ............. 395
Indicator 7: Traceability ...................................................................................................... 397
Dr J.G. Loeber, clinical chemist, head of laboratory, RIVM, LIS department, Bilthoven
(Chapter 9: Indicators)
Dr A. Castel (up to and including February 2009)
Dr Y.B. de Rijke, (as of March 2009), clinical chemist, Erasmus Medical Centre, department
of Clinical Chemistry, Rotterdam
Netherlands Association of Anaesthesiology Employees
H.E. Polak, anaesthesiology nurse, Via Sana Clinic, Mill
Netherlands Association for Surgery
Prof. R.J. Porte, University Medical Centre, department of Surgery, Groningen
Netherlands Orthopaedic Association
W.G. Horstmann (up to and including March 2009)]
D.B. van der Schaaf, orthopaedic surgeon, Sint Maartens Clinic, Orthopaedics department,
Nijmegen (as of April 2009)
Advisor in a personal capacity
Prof. E. Buskens, Professor MTA, UMCG department of Epidemiology, Groningen
H. Vrielink, Sanquin Blood Supply, Amsterdam (as of 01-04-2008)
With special thanks to
Prof. W.G. van Aken, internist n.p. The core group thanks Mr van Aken for his critical
evaluation of the draft texts and his suggestions for improvements.
Acknowledgements
Ms R. Ditz-Kousemaker, Leiden University Medical Centre, Leiden
Ms J.C. Wiersum-Osselton, TRIP
Ms J.S. von Lindern, paediatrician-neonatologist, Groene Hart Hospital Gouda, department
of paediatric medicine
A.R.J. Verschoor (coordinator Hospital information service for Jehovas Witnesses)
Publisher Reed business, Elsevier healthcare
Dr J.L. Kerkhoffs, internist-haematologist, Haga Hospital, The Hague
L.M.G. van de Watering, physician-investigator. Sanquin Blood Supply South-West Region
Dr L. van Pampus, haematologist, UMC St Radboud, Nijmegen
CBO, Utrecht
Mrs D.M. Schipper, CBO advisor, project leader (until 31 October 2010)
Dr P.N. Post, CBO senior advisor, physician-epidemiologist
Mrs C.J.G.M. Rosenbrand, physician, CBO senior advisor (as of 31 October 2008)
Dr J.J.E. van Everdingen, dermatologist, CBO senior advisor (up to and including 31
October 2008)
GENERAL INTRODUCTION
This guideline consists of recommendations for the blood transfusion practice and the
underlying arguments for these recommendations. They were created through study of the
literature and subsequent opinion forming within a multi-disciplinary working group with
delegated representatives from the various professional organisations involved in blood
transfusion.
Introduction
Blood and blood components have a special place within the Dutch healthcare system.
Whereas most other consumables in medicine are supplied by commercial companies,
blood is provided without compensation by voluntary donors (nearly 3 % of the Dutch
population). The health and safety of both patients and donors is central in blood
transfusions. This requires advanced production methods, strict procedures, stringent quality
requirements and checks, regulations and monitoring during the administration. Every
donation is tested, thereby minimising the risk of blood-transferable infections through blood
components. However, despite all precautions, there is still a very small risk of
contamination by blood transfusion. This is part of the reason why caution is advised in the
use of blood and blood components. Claims for damages by patients who received HIV
infected blood were responsible for an international understanding that the liability for the
safety of blood components needed to be improved. What does this mean in practice? In the
Netherlands, Sanquin Blood Supply is responsible for donor care, donor-component linkage
and the safety and efficacy of the component. But what is safe and what is effective? The
hospitals are responsible for effective and correctly indicated use of blood components, the
compatibility study, the component-patient linkage and the registration thereof, but what is
effective and correctly indicated use and how does a patient receive the correct blood
component? The current revision of the Blood Transfusion Policy guideline aims to answer
these questions.
Motivation
The Blood Transfusion Policy guideline is the first guideline created under the auspices of
the Medical Scientific Board of the CBO in 1982. Several revisions have taken place since
then. As a result, this guideline has become a standard work, viewed as a manual by
everyone in the blood transfusion world. Research has also been performed into the extent
to which the guideline is actually followed. One of the most important recommendations from
the first guideline (1982) was that the use of full blood should be limited as far as possible
and that the use of erythrocyte concentrate should be stimulated as much as possible. This
policy has been implemented, but other recommendations from the guideline have not been
followed so successfully. This is due in part to the burden of proof from the literature cited,
but also due to the extent to which risks are deemed acceptable in relation to costs incurred.
On 8 January 2007, the CBO received a letter from the Sanquin Blood Supply National
Users Board, requesting a revision of the Blood Transfusion Policy guideline from 2004.
The revision emphasised in particular a further strengthening of clinical thinking and acting in
the field of blood transfusion.
10
Aim
The aim of the revision was to update the multi-disciplinary guideline on transfusion policy of
blood and blood components from 2004 This consisted of the evaluation of the relevance of
new research data, subjects that were not discussed in the previous version and
developments in the social debate, and incorporation of these matters into the new
guideline.
Part of this involves making recommendations that stimulate a more uniform clinical thinking
and acting in the field of blood transfusion. Confirming the role of nurses in blood
transfusions and incorporating new national initiatives such as the creation of the TRIX
database for irregular red cell antibodies were also important focal points for the revision.
The clinical evaluation of transfusion and clinical transfusion research to support the basis
for guideline development were promoted, and skills improvement of employees involved in
blood transfusion is aimed for, with a focus on the hospital situation. This involves
technicians, nurses and doctors.
Where there continues to be a lack of evidence based knowledge on certain subjects
despite new literature, the working group has based on discussion and consensus
formulated suggestions and recommendations.
This revision also aimed to provide a brief summary of the clinical guideline in pocket-format.
Such booklets (also called Transfusion Guides) have) has previously been developed by
many hospitals. The aim of the present booklet is to nationalise such a pocket guideline.
Parallel to the revision of the guideline, a set of internal indicators based on the guideline
has been developed, aiming for the effective and safe use of blood components. Such
indicators were not present in the 2004 guideline.
An important part of the revision was the development of a more accessible digital version of
the guideline with a uniform and balanced layout of the chapters, clearly showing what has
changed.
In order to improve the accessibility, a search function was implemented from the table of
contents in the PDF guideline document. When the reader clicks the cursor on the desired
paragraph in the table of contents, he/she will be linked to the relevant paragraph.
Target group
The guideline is aimed at all care providers involved in blood transfusions. This guideline is
authorised by the associations that contributed to the development of this guideline. As a
result, this guideline has become part of the professional standard of the members of these
associations.
11
Although this guideline primarily relates to procedures and actions performed in a hospital
setting, the recommendations also apply to blood transfusions outside the hospital, for
example in the independent treatment centres (ITC) and via home care organisations.
Composition of the core group and working group
The blood transfusion policy guideline working group has a multi-disciplinary composition: as
many professionals as possible from various disciplines involved in blood transfusion
were asked to participate. In composing the working group, a balanced representation was
sought of the various disciplines involved, the geographical distribution of the members and
the proportion of academic to non-academic institutions. Members of the working group were
invited to take part in the working group via the relevant (scientific) associations based on
their personal expertise and/or affinity with the subject. They did not receive any payment
and/or reimbursement of travel costs for their presence at working group meetings. A small
core group was formed from the members of the working group. The working group was
chaired by two chairmen, who also acted as chairmen for the core group. The working group
members and core group members acted independently and were mandated by their
association for participation in the working group. No relationships relevant to this guideline
of working group members with the pharmaceutical industry were reported.
Core group working method
The primary task of the core group was to monitor the progress of the entire process,
including the results of the working group. The core group members were each responsible
for the end result of one or more chapters. The core group also collaborated with the CBO in
the final editing of the guideline.
Working group working method
The working group worked on the creation of a draft guideline over a period of two and a half
years. The entire working group met on several occasions for plenary discussion,
development and approval of the draft texts. The working group worked in small sub-groups
outside the plenary meetings on the revision of chapters for the guideline. Some working
group members were involved in the revision of several chapters. For each chapter, one
working group member was responsible for the revision of the chapter, supported by the
core group member(s) with ultimate responsibility.
A literature search was performed for each question according to the Evidence-Based
Guideline Development (EBGD) method, in cooperation with an advisor from the CBO. The
initial search looked for evidence-based guidelines and reviews in the period from the end
date for inclusion of the literature in the previous revision (early 2003) up to and including
February 2008. The guidelines and reviews that were found were evaluated for quality by the
chairmen with the aid of the AGREE instrument. If a valid guideline and/or review was found,
the evidence from the guideline was used to answer the initial questions. Next, the working
group members searched for additional studies per chapter from the moment at which the
search in the guideline and/or review ended.
The project also offered scope for the CBO to develop seven initial questions. The CBO
information specialist performed a systemic literature search from the moment at which the
search in the guideline and/or review ended. This was performed based on search criteria
set by the sub-working group in advance. The sub-working group, which studied the relevant
12
question, then selected the articles based on the quality and content, after which the CBO
information specialist wrote the draft evidence text. These draft evidence texts were then
evaluated by the relevant sub-working groups and supplemented with other considerations
from the practical setting and recommendations based on the conclusions from the scientific
literature and these other considerations.
All draft texts were discussed several times in the plenary working group, commented on
and eventually approved.
Working method for guideline development
The Blood Transfusion Policy guideline project was financed by The Netherlands
Organisation for Health Research and Development (ZonMw) within the programme
Knowledge Policy Quality of Curative Care. Members of the working group and the core
group worked on the development of the guideline for more than two and a half years
(November 2007 July 2010).
The revision started with an inventory of the bottlenecks observed in practice with the Blood
Transfusion guideline from 2004, which served as a starting point for the revision. The
working group members were asked to consult their association members to name and
create an inventory of these bottlenecks. The relevant patient groups (see also under
patient perspective) were also asked to name and create an inventory of the bottlenecks
that they experience in the practical situation. Once the bottlenecks had been collected, they
were categorised in the relevant chapter. Seven initials questions were distilled from the
prioritised bottlenecks for elaboration by a CBO advisor. As a result, the working group
decided to change the layout of the guideline and divide the chapters according to specific
problems, whilst still maintaining the indications. This was also done to improve the
accessibility of the guideline.
The guideline was then revised according to the procedure described under core group
working method and working group working method. Texts developed by the working group
were then edited by the core group and the CBO to form the draft guideline. Prof. W.G. van
Aken, internist n.p. read the draft texts in the final phase critically and made suggestions for
improvement.
The draft guideline, which could be consulted via the CBO website, was submitted to the
relevant associations with mandated representatives in the working group for a consultation
round. The relevant groups listed under patient perspective were also specifically asked to
comment on the Blood Transfusion draft guideline. The resulting comments were processed
in the definitive draft guideline. Following inclusion of the comments, the draft guideline was
submitted to the associations for authorisation and it was approved on 1 August 2011.
13
14
Damage or
prognosis*
adverse
effects,
etiology,
A1
Systematic review of at least two studies performed independently of each other at level A2
A2
Randomised,
double-blind,
comparative clinical study of good
quality and sufficient size
Non-comparative study
Expert opinion
* This classification only applies in situations where controlled trials are not possible due to ethical or other reasons. If these are possible, then
the classification for interventions applies.
Level of conclusions
Conclusie gebaseerd op
1
Research of level A1 or at least 2 studies performed independently at level A2, with consistent results
1 study at level B or C
Expert opinion
15
Other considerations
In order to make a recommendation, in addition to scientific proof, there are also other
important aspects such as patient perspective, organisational aspects and costs. These
were discussed under the heading Other considerations.
Recommendation
The recommendation that was ultimately formulated is the result of the scientific conclusion,
which also included the other considerations.
Literature
Each chapter ends with a literature list of the references cited in that chapter.
Patient perspective
There is no specific patient organisation that looks after the interests of the population of
patients undergoing blood transfusions. Therefore, there was no representative from a
specific patient organisation in the blood transfusion guideline working group. There are
specific patient groups who are confronted with blood transfusions to a greater extent.
Therefore, it was decided in this revision, to include these patient groups in the inventory of
the bottlenecks which formed the basis for the revision, and to submit the draft guideline for
commentary to these same patient groups during the consultation phase. The aim was to
guarantee the input of patient groups involved in blood transfusion during the revision
process. The following patient groups were approached and cooperated in this matter:
OSCAR Netherlands (sickle cell disease and thalassaemia)
Association for Parents, Children and Cancer
Contact Group for Kahler and Waldenstrm Patients
National Association for Dialysis and Transplantation
Association for Parents of Incubator Children
Kidney Patients Association of the Netherlands
As Jehovahs Witnesses have a specific stance against blood transfusions due to religious
convictions, the Association of Jehovahs Witnesses was also approached to think about
bottlenecks in the practical situation and to comment on the draft guideline during the
commenting phase.
Authorisation, dissemination and implementation
The draft guideline was submitted for authorisation to all scientific and professional
associations involved. The guideline was then authorised by the relevant associations and
authorities. The guideline was then initially disseminated through the websites of these
parties that were involved and made available through the website of the CBO www.cbo.nl.
The direct link is www.cbo.nl/bloedtransfusie. The definitive guideline will be disseminated
amongst the associations and will be available in digital format. The recommendations of the
guideline will be presented at scientific meetings of the relevant scientific associations. An
announcement of this guideline will be submitted for publication to the Netherlands Journal
of Medicine, the Journal for Blood Transfusion and the Netherlands Journal of Clinical
Chemistry and Laboratory Medicine.
16
In order to stimulate the implementation and evaluation of this guideline, internal indicators
have been developed, which allow for the implementation to be measured by random
sampling. In general, indicators give the care providers the opportunity to evaluate whether
they are providing the desired care. This enables them also to identify subjects for
improvement of the care provision. The internal indicators that were developed for this
guideline are discussed in chapter 9 of this guideline.
Legal significance of guidelines
Guidelines are not legal instructions, but rather scientifically substantiated and/or broadly
accepted insights and recommendations that care providers should follow in order to offer
good quality care. As guidelines are based on the average patient, care providers can, if
necessary, deviate from the recommendations in the guideline in individual cases.
Sometimes it may even be essential to deviate from guidelines if the patients situation
demands this. However, if a conscious decision is made to deviate from the guideline, a
case must be made for this and it must be documented. One should also consider whether
this should be discussed with the patient, or whether the patient should be informed.
Revision
This guideline will be evaluated for relevance no later than the end of 2015. If necessary, a
new working group will be created to revise (parts of) the guideline. The validity of the
guideline will expire sooner if new developments form a reason to start the revision process.
We have asked the Netherlands Association for Blood Transfusion, the Association for
Haematological Laboratory Research and the National Users Board of Sanquin Blood
Transfusion to develop a structural approach for the stimulation of the implementation of the
Guideline particularly by the clinical departments such as monitoring the relevance and
for the revision of this Guideline or parts thereof.
17
18
Characteristic
Specifications
(average)
erythrocytes
270 mL
that
have Ht 0.57 L/L
undergone
< 1 x 106
filtration
to leukocytes
remove
most <20 mL plasma
leukocytes and
platelets
Erythrocytes,
ditto, irradiated
leukocytes
(25 Gy)
removed and
irradiated,
in
storage solution
ditto
ditto
ditto
for
paediatric O RhD neg. or
use (Pedi-bag)
O RhD pos.
60 mL
Ht 0.57 L/L
ditto
for
paediatric
use irradiated
(Pedi-bag)
Erythrocytes,
leukocytes
removed,
in
added
citrate
plasma
(exchange)
Erythrocytes
Leukocytes
removed
and
washed,
in
storage solution
Shelf-life
Indication
35 days
at 2 6 C (in
special
blood
storage
refrigerator)
Symptoms
of
shortage
of
oxygen
transport
capacity, either
due to blood
loss or as a
result of severe
anaemia
irradiated < 14 d See table 2.1
after collection:
max
28
d;
irradiated > 14 d
after collection
max 24 h
35 days at
Ditto
for
2 6 C
neonates
24 hours after
See table 2.1
irradiation at 2
6 C
erythrocytes (<
5 days), where
storage solution
has
been
replaced by AB
plasma
erythrocytes
from which
as much plasma
as possible has
been removed
by washing
Volume: 365 mL
Ht 0.45 L/L
24 hours after
Exchange
preparation at 2 transfusion
6 C
260 mL
Ht 0.57 L/L
<1x106 leukoc.
<0.2 mL plasma
19
Characteristic
Platelets
leukocytes
removed in
storage solution
(irradiated or not)
platelets with
strongly
reduced
leukocyte levels
made from the
buffy coat of the
blood from 5
donors
Platelets,
Leukocytes
removed in
plasma
ditto
Apheresis
platelets,
leukocytes
removed
platelets
produced via
apheresis
procedure from
one donor in
storage
solution or
plasma
platelets
in plasma or
storage solution
produced via
apheresis
procedure
leukocytes
removed from
platelets in
plasma,
concentrated
Apheresis
platelets,
leukocytes
removed for
paediatric use
Platelets
hyperconcentrate
Plasma,
apheresis, fresh
frozen
Plasma,
apheresis, fresh
frozen split
20
minimum
year in
quarantine for
storage
leukocytes
removed
ditto
Specifications
(average)
310 mL
340 x 109
platelets
< 1 x 106
leukocytes
< 5 x109
erythrocytes
storage
solution: PAS II
(65 %)
Shelf-life
Indication
administer as
soon as
possible after
receipt, but no
more than 6
hours after
receipt
1. Thrombocytopenia
2. In case of severe
bleeding due to
thrombocytopathy
NB Preferably
administer ABO
compatible
(platelets), RhD
compatible for
women < 45 years of
age
ditto
340 mL
340 x 109
platelets
< 1 x 106
leukocytes
< 5 x 109
erythrocytes
320 mL
360 x109
platelets
leukocytes <
1x106
ditto
ditto
65 ml
ditto
platelets for
neonates
administer as
soon
as possible (<
3 hours
after
production)
administer as
soon as
possible after
thawing and
within 6 hours
ABO incompatibility,
volume overload,
allergic reactions to
plasma
ditto
ditto
58 x 109
platelets
adults < 20 mL
paediatric 7
10 mL
325 mL
< 1 x 106
leukocytes
> 70 % of all
clotting factors
75 ml
ditto
see 2.2.3
2.1
21
22
Plasma proteins have been removed from the standard component (erythrocytes, leukocytes
removed, in SAGM) as much as possible by washing with NaCl 0.9 % or SAGM, after which
the erythrocytes are resuspended in approximately 100 mL SAGM. The number of
erythrocytes is at least 135 mL (40 g Hb), the haematocrit is 0.50 0.65 L/L. Due to the
washing, the unit contains very little IgA, allergens and complement. The number of washes
performed is either 2 (prevention of allergic reactions) or 5 (prevention of reactions due to
IgA deficiency).
If the washing is performed for a patient with IgA deficiency, the plasma protein in the final
component should be < 30 mg.
Leukocytes removed, frozen stored and thawed
Erythrocytes that are eligible for freezing are obtained from selected donors who lack certain
blood group antigens; or from designated autologous collections (patients) in specific
situations. The component is prepared by removing the storage solution from a unit of
erythrocytes (either buffy coat removed, or leukocytes removed) and adding glycerol as a
cryo-protectant. These units are stored centrally in the Sanquin Bank of Frozen Blood
(SBFB). The erythrocytes are selected for antigen typing, leukocytes removed and stored at
-80 C or -196 C after the addition of glycerol. After thawing, the units are washed with
physiological saline solution with decreasing concentrations of glucose. Finally, they are
resuspended in SAGM.
The quantity of erythrocytes is at least 135 mL (40 g Hb) in physiological saline, with minimal
traces of glycerol. The volume is usually 210 225 mL, with a haematocrit of 0.55 0.65
L/L. As a result of the washing, the unit contains very few plasma proteins and little extracellular potassium, sodium and glucose. Depending on the original erythrocyte component,
the number of leukocytes is 1 x 10 6 or less and there are no platelets present (see also
paragraph 2.2.1).
CMV negative / Parvo B19 safe
Although erythrocytes leukocytes removed can be considered Cytomegalovirus (CMV)
safe, tests for the presence of CMV antibodies are performed if there is a specific indication.
The absence of CMV antibodies indicates CMV antigen negativity. A validated test is used
for this purpose. This is a characteristic of the component and not the donor. Each
component should be tested again.
Parvo B19 safe blood components are obtained from donors who are positive for antibodies
targeted against the Parvo B19 virus. The presence of anti-Parvo B19 is determined by 2
tests, spaced at least 6 months apart. This is a characteristic of the donor and not the
component. Repeat testing is not necessary.
2.1.3 Platelet characteristics
Introduction
The common platelet component in the Netherlands is prepared from the buffy coats of five
different donors or an apheresis component from one donor. A unit of plasma or a specific
volume of platelet storage solution (platelet additive solution type II (PAS II)) is added during
the production of buffy coat platelets. Apheresis techniques are used if an HLA/HPA typed
platelet component is required. Either plasma or storage solution can be added to apheresis
platelet components.
Blood Transfusion Guideline, 2011
23
Level 1
Level 2
Kerkhoffs 2006
Recommendation 2.1.3
PAS II + plasma can be used instead of plasma as a storage solution for platelets.
Transfusion reactions by anti-A and anti-B in plasma-incompatible platelets
Scientific support
A haemolytic transfusion reaction is a rare, but severe (sometimes fatal) complication of
transfusion of so-called out-of-group platelets, in which a minor ABO incompatibility occurs
(plasma-incompatible platelets). Published case reports concern patients who were
transfused with single-donor apheresis platelet components, from donors with high anti-A
and/or anti-B titres. A retrospective study found one haemolytic transfusion reaction for over
9,000 plasma incompatible apheresis platelet components (Mair 1998). A recent systematic
24
review concluded that ABO identical platelet transfusions for haemato-oncology patients
provided a higher yield and that ABO non-identical platelet transfusions were not associated
with more transfusion reactions (Shehata 2009). Five cases of fatal haemolysis due to
plasma-incompatible platelet components were reported to the FDA over a period of four
years. Fatal reactions were observed primarily in patients with a relatively low circulating
plasma volume, who received relatively large amounts of incompatible plasma over a short
period of time. Neonates and children have a relatively low plasma volume and therefore
form a separate risk group. Transfusion of ABO non-identical platelet components in cardiac
surgery patients was not associated with decreased survival, increased tendency to bleed,
or decreased yield (Lin 2002). The prevalence of anti-A/A,B IgM titres higher than 64 was 28
% in a group of apheresis donors (Harris 2007).
Conclusions 2.1.3
ABO identical platelets provide a higher yield than ABO non-identical
platelets.
Level 3
C
Level 3
Level 3
Mair 1998
Level 3
Mair 1998
Level 3
Shehata 2009
Lin 2002
Harris 2007
Other considerations
The anti-A and anti-B titres vary according to the determination method used. The difference
in IgM and IgG class antibodies should also be taken into consideration. Titre determinations
can show intra-individual and inter-individual variations. The determination of the correct
anti-A and anti-B titres should take place according to a set protocol, using a standardised
Blood Transfusion Guideline, 2011
25
method. Sanquin Blood Supply performs titre determinations using the salt technique. In the
case of transfusion with incompatible plasma in neonates, the anti-A and/or anti-B titre
should be less than 128. The acceptable limit of a dilution of 1:64 for anti-A/B antibodies
measured in salt is in line with internationally used methods and limits. (International Forum
2005).
Recommendation 2.1.3
1.
Neonates and children should preferably be transfused with ABO identical platelets.
Recommendation* 2.1.3
1.
The determination of the anti-A and anti-B titres in blood components should take
place according to a set protocol, using standardised methods.
2.
When used in newborns up to and including the age of 3 months, combined platelet
components (in plasma or PAS II) or apheresis platelet components may not contain
anti-A IgM or anti-B IgM antibodies at a dilution greater than 1:64.
Leukocytes removed, five buffy coats combined in PAS II (platelets or platelets in
storage solution)
The component is prepared by combining five buffy coats from identical ABO and RhD blood
group with a mixture of plasma and platelet storage solution (PAS II) in a ratio of 1:2. The
cells are then centrifuged to achieve sedimentation so that the upper platelet suspension can
be separated and filtered. The volume of the component is 150 400 mL, the number of
platelets is at least 250 x 109 and no more than 500 x 109. The remaining number of
leukocytes is less than 1 x 106.
Leukocytes removed, five buffy coats combined in plasma (platelets or platelets in
plasma)
The component is prepared by combining five buffy coats from never-transfused male
donors with identical ABO and RhD blood group with plasma from one of.these 5 donors.
The cells are then centrifuged to achieve sedimentation so that the upper platelet
suspension can be separated and filtered.
As a general rule of thumb, the dose for an adult is one platelet concentrate. The volume of
the component is 150 400 mL, the number of platelets is at least 250 x 10 9 and no more
than 500 x 109. The remaining number of leukocytes is less than 1 x 106.
Leukocytes removed, apheresis (apheresis platelets)
Apheresis platelets (single donor platelets) are obtained from one donor. The donor is often
selected ,for instance for CMV sero-negative status if the component is to be used for an IUT
or HLA and/or HPA identical or compatible to match a patient with HLA and/or HPA
antibodies and refractory for combined platelet components. An apheresis machine is used
to harvest platelets from a donor, which are then suspended in plasma from the donor or in a
mixture of plasma and platelet storage solution. Leukocyte removal takes place using the
apheresis machine, or by passing the concentrate through a leukocyte removal filter. The
volume of the component is 150 400 mL, with a target value for the number of platelets of
at least 250 x 109 and no more than 500 x 109. The remaining number of leukocytes is less
than 1 x 106. The volume of storage medium is adjusted to maintain the pH between 6.8 and
26
7.4 and to guarantee the presence of the swirling effect, a visual check for normal
morphology of the platelets by swirling the component.
The more plasma the storage medium contains, the more plasma proteins are present.
However, labile clotting factors are virtually absent, the potassium concentration is
physiological, the sodium concentration is slightly elevated, the glucose level varies between
physiological and slightly elevated depending on the storage medium. There are virtually
no free calcium ions present, the citrate concentration varies from 15 to 25 mmol/L. The pH
and the glucose level decrease during storage and the lactate concentration increases.
The component contains leukocyte antigens and platelet antigens from only one donor. In
the case of apheresis components from selected donors, the apheresis component may not
meet the current guideline in all requirements, for example the dosage. If this is the case, the
treating doctor should be consulted to decide about the use after considering availability and
safety.
Paediatric use
This blood component can be split for paediatric use, with a minimum dose of 50 x 10 9
platelets in a volume of 40 70 mL. In that case, the plasma may not contain any clinically
relevant irregular antibodies targeted against erythrocytes. If incompatible plasma (for
example from an O donor to an A or B patient) must be used for a neonate, the titre of anti-A
IgM and/or anti-B IgM must be less than 128.
2.1.4 Platelet hyperconcentrate
A platelet hyperconcentrate is obtained by taking a platelet component (obtained from
apheresis or after centrifugation of five donor buffy coats) and perform further concentration
by extra centrifugation and then resuspending it in a small volume of plasma (15 20 mL).
The component is drawn up into a syringe. Depending on the desired amount of platelets to
be administered, the entire component or part thereof is used (paediatric 7 10 mL). Due to
the very limited shelf-life of only 3 hours for this component, it is prepared only upon
indication.
Platelet component in 100 % PAS II
One tenth (10 %) volume ACD (acid citrate dextrose) is added to a 5-donor platelet
component in PAS II. This component is concentrated after centrifugation to a platelet
pellet, which is then resuspended in PAS II storage solution. This component contains
virtually no plasma. Due to the very limited shelf-life of only 3 hours for this component, it is
prepared only upon indication (following consultation with the KCD of Sanquin Blood
Supply).
2.1.5 Plasma, characteristics
In the Netherlands, the component: fresh frozen plasma, virus-protected by means of a
quarantine method, is used for administration to patients. This component is also
abbreviated as FFP (fresh frozen plasma) and any further mention of plasma in the text
refers to this component. Plasma is obtained by plasmapheresis of male donors without a
transfusion history.
27
Other (commercial) plasma components (including ESDEP) are also available. The position
of these components with respect to the quarantine plasma supplied by Sanquin Blood
Supply is not yet clear and this should be investigated. Also see Chapter 6 Platelet and
plasma transfusion policy.
Plasma contains normal levels of stable clotting factors, protease inhibitors,
immunoglobulins and albumin. The concentration of factor VIII and other unstable clotting
factors is at least 0.70 IU/mL.
The volume of one unit is approximately 325 mL. The protein concentration and the
potassium concentration are physiological, the sodium concentration is elevated to
approximately 168 mmol/L and the glucose level is physiological if sodium citrate is used.
The citrate concentration is between 15 and 25 mmol/L. As a result of the use of citrate anticoagulant, the component contains virtually no free calcium ions.
The component contains fewer than 1 x 10 6 leukocytes and virtually no platelets. If prepared
by means of plasmapheresis using a cell free apheresis method, the component contains
fewer than 1 x 108 erythrocytes. In that case, the risk of RhD immunisation 1 by the
component is considered negligible (see 3.9).
The unit of plasma is released for administration to patients if the donor has been tested with
all the current tests for infectious diseases for a second time ,at least 6 months after the
donation,and subsequent tests have again proved to be negative.
1: Comment: Transfusions of cellular blood components, transplantations and/or
pregnancies form risks of immunisation against blood cells.
Recommendation* 2.1.5
Other (commercial) plasma components (including ESDEP) are also available. The position
of these components with respect to the quarantine plasma supplied by Sanquin Blood
Supply is not yet clear and this should be investigated.
2.1.6 Granulocytes, characteristics
Granulocyte components are collected in a few university hospitals and supplied by Sanquin
Blood Supply as an extemporaneous component.
No fixed component specifications have been agreed upon due to the large individual donor
and patient variation. However, regarding the number of granulocytes per component and in
accordance with the European Guidelines, a minimum of 1 x 10 10 granulocytes per
component is advised (Guidelines for the preparation, use and quality assurance of blood
components; Council of Europe). The initial dose of granulocytes per kilogram of body
weight for the patient is preferably > 8 x 108/kg.
Granulocytes are obtained by means of granulocyte apheresis from selected family
members or donors who are otherwise related to the patient. The granulocytes need to be
mobilised in the peripheral blood prior to the apheresis procedure. This is achieved by
administering G-CSF (5 g/kg subcutaneous) and if a greater yield is required this is
combined with dexamethasone (8 mg oral). Hydroxy ethyl starch (HES) is used to optimise
the centrifugal separation of granulocytes and erythrocytes. The component is harvested in
28
plasma and in addition to the HES contains the anti-coagulant sodium citrate necessary
for the apheresis.
The possible HLA incompatibility of donors related to the patient and the immunocompromised situation of the patient make irradiation (at least 25 Gy) of the granulocyte
component essential. The time required for donor preparation and donor approval is 24-48
hours; the component can only be supplied after this time. See also 2.2.8.
An alternative source that will not be discussed here is the preparation of granulocyte
transfusions from pooled buffy coats generated by the preparation of the whole blood
component from regular blood donors.
2.2
2.2.1 Erythrocytes
Introduction
The indication for administering erythrocytes is based on medical factors and is aimed at
treating or preventing the symptoms of a lack of oxygen transport capacity by the blood.
The Hb value at which transfusion is deemed necessary varies greatly with the age of the
patient and additional illness(es), and is ultimately determined by the treating doctor. A
distinction is made between acute and chronic anaemia. Different Hb values apply for intrauterine transfusions and transfusions in neonates (see Chapter 4. Chronic anaemia and
Chapter 5. Acute anaemia due to blood loss). The standard component for erythrocyte
transfusion is: erythrocytes, leukocytes removed, in storage solution.
Transfusion of erythrocytes can also be used to promote haemostatis in the case of ongoing
blood loss.
Dosage indication for an adult patient: 1 unit of erythrocytes results in an increase in Hb of
0.5 to 0.6 mmol/L. Also see Chapter 4. Chronic anaemia and Chapter 5. Acute anaemia due
to blood loss.
Recommendation* 2.2.1
The indication for administering erythrocytes is based on medical factors and is aimed at
treating or preventing the symptoms of a lack of oxygen transport capacity by the blood.
Exchange transfusion
The most important indication for exchange transfusions is severe hyperbilirubinaemia
(unconjugated bilirubin) due to blood group antagonism in neonates.
For neonates, the total volume of blood that needs to be exchanged (with the aid of a
syringe) is 160 mL/kg body weight ( 2x the circulating volume). A special blood warmer
should preferably be used. During each exchange round at a speed of 2 3 minutes/round
blood is removed from the child and an equal volume of donor blood is returned. Each
round consists of a exchange of 10 mL for a child weighing 1000 1500 grams, 15 mL for a
child weighing 1500 2250 grams and 20 mL for a child weighing more than 2250 grams.
The platelet number is maintained above 100 x 10 9/L during the exchange transfusion
procedure. The platelet number is approximately halved during the exchange. Therefore, the
29
platelets are substituted during and after the exchange transfusion procedure, if necessary,
using apheresis platelets from one donor. Specific precautions and follow-up checks apply
during exchange transfusions for neonates (see Chapter 4. Chronic anaemia).
However, in addition to blood group antagonism, there can also be other causes for
increased haemolysis. Polycythaemia (Ht > 0.65 L/L in venous blood) can form an indication
for partial exchange transfusion (exchange transfusion with physiological saline). Another
indication for exchange transfusions is severe sickle cell crisis (see paragraph 4.4.1 Acute
indications for blood transfusion in sickle cell disease).
Recommendation 2.2.1
1.
2.
3.
Washed erythrocytes
The aim of washing is to remove plasma proteins. There are few indications for washed
components. Components are washed 2 times for patients with a severe allergic reaction to
plasma proteins. Patients with IgA deficiency may have an indication for erythrocyte
components that have been washed 5 times (see also Chapter 7.2.3 Anaphylactic
transfusion reaction).
Recommendation* 2.2.1
The washing of erythrocyte components is recommended for patients with a severe allergic
reaction to plasma proteins (wash 2 times) and for patients with IgA deficiency (wash 5
times).
Frozen, stored and thawed
If a patient has (or has had) clinically relevant, rarely occurring irregular antibodies against a
very frequently occurring blood group (HFA = high frequency antigen), or against a rare
combination of blood groups, this forms an indication for the administration of erythrocytes
that are negative for the corresponding antigen(s). Such rare compatible erythrocytes are not
present in the regular stocks of Sanquin Blood Supply, but are frozen and stored at a central
location: Sanquin Bank of Frozen Blood. (Auto-transfusion or designated donation can be
considered as alternatives.) Information about frozen, stored erythrocytes can be obtained
through the Clinical Consultation Service of Sanquin Blood Supply.
In addition to filtered erythrocytes, the stock of frozen erythrocytes also contains
erythrocytes, buffy coat removed. These components do not meet the criteria for general
leuko-reduction, because approximately 10 9 leukocytes were present before freezing. It is
30
possible that due to the erythrocyte typing, these non-leukocyte removed erythrocytes are
the only suitable option. The treating doctor will have to decide between transfusing this
component and not performing the transfusion (in the absence of an alternative). A doctors
declaration is required if a non-leukocyte removed component needs to be supplied.
Recommendation* 2.2.1
The working group is of the opinion that the administration of frozen, stored and thawed
erythrocytes that are negative for the corresponding antigen is indicated if the patient has (or
has had) clinically relevant, rarely occurring irregular antibodies against a very frequently
occurring blood group (HFA = high frequency antigen), or against a rare combination of
blood groups.
2.2.2 Platelets
General
The administration of platelets aims to improve primary haemostasis in order to decrease the
tendency to bleed or to treat an existing bleed in patients with thrombocytopenia or
thrombocytopathy.
It is important that the cause of the thrombocytopenia or thrombocytopathy is established
first.
For invasive procedures, the risk of the procedure in relation to blood loss should be
established. Only then can the correct treatment be selected, in which the administration of
platelets can play a role, in addition to other (medicinal, surgical) measures that reduce the
blood loss.
The standard component is platelets that have been obtained from the buffy coats of five
ABO/RhD identical donors, in plasma or PAS II.
Dosage indication for adults: 1 unit of platelet concentrate yields a platelet increase of 20
50 x 109/L within 10 minutes or a CCI of > 7.5. Also see Chapter 6 Platelet and plasma
transfusion policy.
Recommendation* 2.2.2
1. The cause of the thrombocytopenia or thrombocytopathy should always be
establishedbefore opting for the administration of platelets.
2. For invasive procedures, the risk of the procedure in relation to the tendency to bleed
should be established first. The correct treatment is then selected. In addition to
medicinal and/or surgical measures to reduce blood loss, the administration of
platelets can be considered.
Platelet hyperconcentrate
Recommendation* 2.2.2
The use of platelet hyperconcentrate can be considered for neonatal and paediatric use in
order to prevent volume overload. Minor ABO incompatibility, allergic reactions to plasma
and volume overload can be considered as indications for the use of platelet
hyperconcentrate. (see Chapter 6. Platelet and plasma transfusion policy for details)
31
2.2.3 Plasma
Plasma is indicated for substitution of deficient clotting factors in:
Thrombotic Thrombocytopaenic Purpura = TTP (ADAMTS-13) and non-STEC
HUS1/atypical Haemolytic Uraemic Syndrome = atypical HUS (factor H)
Plasma can be indicated in:
bleeding associated with combined clotting factor deficiencies due to:
- loss/dilution with crystalloids and/or colloids during massive
transfusions or plasmapheresis
- acute disseminated intravascular coagulation
- severe liver insufficiency
- isolated deficiency of factor V (non-recombinant/purified available)
to counteract the effect of fibrinolytics (recombinant tissue plasminogen activator,
streptokinase and urokinase) and L-asparaginase therapy;
during plasmapheresis for thrombotic micro-angiopathies other than TTP or atypical
HUS in adults.
1
: STEC HUS = Shiga-like toxin-producing E. coli-associated HUS
Other considerations
As a rule of thumb, a coagulation profile is performed to determine the extent of deficiency
for all indications, with the exception of TTP. However, in clinical practice there are situations
(such as massive blood loss) in which it is not feasible to wait until clotting deficiencies have
been demonstrated before administering plasma. The doctor can also decide to administer
plasma components based on his/her observations, without test results. With respect to the
frequently mentioned target value of 1.0 g/L for fibrinogen, this value may possibly be suboptimal for effectively stopping uncontrolled blood loss or adequately compensating for blood
loss, see also 5.3.2.3. Evaluation of the effect of the administration of plasma can be
performed afterwards in this case.
Dosage indication for adults: 10 15 mL/kg. See also Chapter 6 Platelet and plasma
transfusion policy.
The effect of administration of plasma should be evaluated based on a coagulation profile.
Recommendation* 2.2.3
Plasma is indicated for substitution of deficient clotting factors in:
Thrombotic Thrombocytopaenic Purpura = TTP (ADAMTS-13) and non-STEC
HUS1/atypical Haemolytic Uraemic Syndrome = atypical HUS (factor H)
Plasma can be indicated in:
bleeding associated with combined clotting factor deficiencies due to:
loss/dilution with crystalloids and/or colloids during massive transfusions or
plasmapheresis
acute disseminated intravascular coagulation
severe liver insufficiency
isolated deficiency of factor V (non-recombinant/purified available)
to counteract the effect of fibrinolytics (recombinant tissue plasminogen activator,
streptokinase and urokinase) and L-asparaginase therapy;
during plasmapheresis for thrombotic micro-angiopathies other than TTP or atypical
HUS in adults.
32
If the term blood components is used in this paragraph , this refers to erythrocyte concentrates, with the
exception of cryo-preserved erythrocytes, and platelet concentrates, so no plasma or fractionated plasma
components.
33
Recommendations* 2.2.4
1.
It is deemed useful to follow the British guideline from the BCSH for the indications of
administration of irradiated blood components. Please refer to table 2.1 Indications for the
use of irradiated blood components.
2.
The international guidelines are also followed for premature babies as they can have
cellular immune disorders.
3.
Patients who are participating in a study protocol using (possibly) immuno-suppressive
medicines and who are therefore (possibly) at increased risk of Transfusion-Associated
Graft versus Host Disease (TA-GvHD) should receive irradiated blood components.
2.2.5 Indication for CMV-safe and CMV (sero)-negative components
The CMV-virus is primarily associated with lymphocytes. Therefore, leukocyte-removed
blood components are considered CMV-safe (Kuhn 2002, James 1997, Adler 1988, Smith
1993, Roback 2000). CMV sero-negative tested components are components that have
been tested for the presence of CMV antibodies and have been found negative. The title
CMV negative is a characteristic of the component and not a donor characteristic. In one
controlled study, primary CMV infections were found in 1.3% of recipients of CMV seronegative tested blood components and in 2.4% of the recipients of leukocyte-reduced blood;
this difference was not statistically significant (Bowden 1995). Leukocyte-removed
components can therefore be considered as CMV-safe (Preiksaitis 2000, Laupacis 2001).
Conclusion 2.2.5
34
A2
Kuhn 2002, James 1997, Adler 1988, Smith 1993, Roback 2000,
Bowden 1995, Preiksaitis 2000, Laupacis 2001
Other considerations
The risk of CMV contamination is very low with general leuko-reduction, but can never be
eliminated completely. This is one of the reasons why, in the case of intra-uterine
transfusions, the treating experts wish to administer cellular components that not only have
had the leukocytes removed, but also are CMV tested sero-negative to (immunocompromised) foetuses.
Extremely premature babies (< 32 weeks and/or < 1500 g) are also considered severely
immuno-compromised. For these reasons and due to the risk of sepsis-like illness, various
Western countries opt to administer only CMV sero-negative components to extremely
premature babies.
Recommendations* 2.2.5
1.
2.
35
antibodies against B19. IgG antibodies against B19 neutralise the virus and give lifelong
immunity. The risk of transfer of B19 through blood components from a donor with these
antibodies is therefore extremely low.
The following Parvo-safe components are available: erythrocytes, platelets and plasma.
The indications summarised in table 2.2 are listed in the publication by the Health Council
Blood components and Parvo virus B19 (Health Council 2002). The evidence for this is level D
(expert opinion).
Table 2.2: Indications for Parvo B19 safe blood components (Health Council 2002)
1. Unborn babies receiving intra-uterine transfusions (IUT)
2. Premature babies (< 32 weeks and/or < 1500 grams)
3. Neonates following IUT, for 6 months after the due date
4. Pregnant women (only in case of transfusion during pregnancy)
5. Patients with congenital or acquired haemolytic anaemia, who do not have antibodies against
B19.
6. Patients with a cellular immune deficiency, who do not have antibodies against B19.
Recommendations* 2.2.6
The working group supports the indications for administration of Parvo B19 safe blood
components from the Health Council Report of 2002. These indications are:
1.
Unborn babies during intra-uterine transfusions (IUT)
2.
Premature babies (< 32 weeks and/or < 1500 grams)
3.
Neonates following IUT, for 6 months after the due date
4.
Pregnant women (only in case of transfusion during pregnancy)
5.
Patients with congenital or acquired haemolytic anaemia, who do not have antibodies
against B19.
6.
Patients with a cellular immune deficiency, who do not have antibodies against B19.
2.2.7 Indication for washed cellular components and IgA deficient plasma
There is an indication for washing of cellular components in patients who (could) experience
a severe transfusion reaction against plasma proteins. The aim of the washing is to reduce
the remaining plasma protein level in the unit. See also Chapter 7.2.3 Anaphylactic
transfusion reaction.
Recommendation* 2.2.7
Washing of cellular components for administration to patients who (could) experience severe
transfusion reactions against plasma proteins is recommended. The aim of the washing is to
reduce the remaining plasma protein level in the unit. See also Chapter 7.2.3 Anaphylactic
transfusion reaction. Also refer to recommendation 2.2.1 Washed erythrocytes.
36
Level 3
Level 3
Level 4
Stanworth 2005
37
this therapy.
D
Seidel 2006
38
currently being amended for granulocyte transfusions in adults. The aim is also to use a
central database to monitor all granulocyte transfusions and if possible to compare the
treated patients with matched controls who do not receive granulocyte transfusions despite
having a potential indication. Such a case-control study will hopefully generate more
evidence for the efficacy of granulocyte transfusions.
Recommendations 2.2.8
1. Despite the theoretical importance and case reports that suggest the benefit of
granulocytes as adjuvant therapy for severe systemic and treatment-resistant
infection in granulocytopaenic patients, there is insufficient convincing scientific
evidence to support or reject this treatment.
2. So far, granulocyte transfusions have to be considered as a compassionate need
treatment that is not without risks.
3. Experience concerning donor approval, donor information, donor care (during
mobilisation and collection), donor follow-up, additional component preparation,
patient selection and follow-up are of utmost importance.
4. For the entire granulocyte transfusion chain from donor to patient, the aim is to achieve
uniform treatment guidelines (SKION / NVvH) and to combine and exchange data.
5. Granulocyte transfusions should preferably take place in the framework of (inter)national
studies.
If a granulocyte transfusion is to be performed:
1. Donors should be tested for the blood-transmissible diseases HIV, hepatitis B and C,
HTLV-I/II and syphilis.
2. ABO and RhD matching is essential, as is the determination of irregular erythrocyte and
HLA antibodies, and the performance of erythrocyte cross matches and (in the case
of HLA antibodies) granulocyte cross matches.
3. Major or minor ABO incompatibility does not form an absolute contra-indication, but does
create a risk of acute or delayed haemolytic transfusion reactions. In the case of
major or minor incompatibility between the donor and the patient, measures (tailored
to antibody titres) should be implemented to reduce the number of red blood cells
and plasma if relevant.
4. Reactive HLA and/or HNA antibodies between donor and patient should be considered
as a contra-indication for the donor involved.
5. The short and long term risks to the donor of the administration of G-CSF and side
effects of HES should be taken into consideration.
6. A described and recorded information procedure concluding with informed consent of
the donor must be present. A maximum number of G-CSF stimulations per donor
(usually three times) should also be set. Donor centres should also formulate a
follow-up policy for possible undesirable severe adverse effects (SAEs) in donors.
2.3
2.3.1 Introduction
The storage conditions, the shelf-life and the requirements for the transportation of blood
components are set by Sanquin Blood Supply . Storage systems for blood components must
39
meet the requirements for Good Manufacturing Practice (GMP). This includes the
requirement that it must be fitted with a (continuous) temperature registration system and an
acoustic alarm, so that measures can be taken to secure the required temperature. The
requirements for minimum and maximum temperatures must also be guaranteed during
transport to the hospital and during storage in the hospital.
There are various storage and transport systems available. These must be validated before
use. The shelf-life of the blood components as indicated on the label by the supplier
applies as long as the component has been stored and transported correctly. The storage
conditions to guarantee the shelf-life of the various blood components must be indicated
exactly under all conditions (both storage and transport) and must be recorded in working
instructions. The temperature of the blood component is recorded from the moment of
donation (whole blood and plasma).
Materials or components other than blood components may not be stored in the blood
storage systems. So-called household refrigerators are not suitable for the storage of blood
components for transfusion.
Recommendations* 2.3.1
1. Storage systems for blood components must meet the requirements for Good
Manufacturing Practice (GMP).
2. Storage and transport systems must be validated before use.
3. The storage conditions for blood components must be indicated exactly for all conditions
and must be recorded in a working instruction.
4. The temperature of the blood component is recorded from the moment of donation
(whole blood and plasma).
5. Materials or components other than blood components may not be stored in the blood
storage systems. So-called household refrigerators are not suitable for the storage of
blood components for transfusion.
2.3.2 Storage conditions, shelf-life and transport of erythrocytes
As far as biochemical composition and shelf-life are concerned, it has been proven that the
best storage temperature for erythrocytes is between 2 C and 6 C. The risk of bacterial
growth is also acceptably low at this temperature. The temperature during storage and
transport may never be lower than 1 C. Unless stated otherwise, erythrocytes have a
maximum shelf-life of 35 days.
If a validated storage system is not in use, erythrocytes should be administered to the patient
within 6 hours of receipt.
The aim should be to keep the component outside the refrigerator (temperature > 10 C) for
no longer than half an hour before administration to the patient. This can mean that
departments where blood is stored (both operating rooms and recovery rooms) for a longer
time (maximum of 24 hours) before transfusion must be fitted with validated blood storage
refrigerators. The hospital is responsible for developing a policy for this.
After opening or inserting a needle/spike into the system, the maximum storage time is
limited to a maximum of 6 hours due to the risks of bacterial growth.
Erythrocyte components that have reached a temperature exceeding 10 C after storage
may not be returned to storage and must be administered within 6 hours or otherwise they
40
41
Vamvakas 2010
Leukocytes removed, washed
If resuspended in SAGM storage solution with the aid of a closed system, washed
erythrocytes can be stored for a maximum of five days at a temperature between 2 C and 6
C in a blood storage refrigerator (Sanquin Guideline Blood Components 2008).
Recommendation* 2.3.2
If resuspended in SAGM storage solution with the aid of a closed system, the washed
component leukocytes removed, erythrocyte concentrate can be stored for a maximum of
five days at a temperature between 2 C and 6 C in a blood storage refrigerator.
Leukocytes removed, frozen stored and thawed
Erythrocytes with a rare typing are stored by Sanquin Blood Service in the Sanquin Bank of
Frozen Blood (SBFB) at a temperature below -150 C (older procedure) or below -80 C
(newer procedure), using a cryo-preservative. These frozen units can be stored for a
maximum of 10 years. The maximum storage time after thawing and washing is a of 24
hours (older procedure) or 48 hours (newer procedure), if the component is stored in a
blood storage refrigerator at 2 C 6 C.
Recommendation* 2.3.2
Frozen erythrocytes from the Sanquin Bank of Frozen Blood, once thawed may be stored in
a blood storage refrigerator between 2 C and 6C, for:
- a maximum of 24 hours after being frozen at a temperature below -150 C (older
procedure);
- a maximum of 48 hours after being frozen at a temperature below -80 C (newer
procedure);
Erythrocytes for intra-uterine and exchange transfusions
Erythrocytes destined for intra-uterine administration and erythrocytes for exchange
transfusions have specific shelf-life requirements.
Recommendations* 2.3.2
1. Pooled blood (consisting of erythrocytes less than 5 days old, from which the storage
solution has been removed and to which citrate plasma has been added) destined for
exchange transfusion should be administered as soon as possible. However, pooled
blood can be transfused up to 24 hours after preparation, provided it has been stored
in a blood storage refrigerator at 2 C 6 C.
2. Irradiated exchange components can as is the case with non-irradiated components
be stored for 24 hours after preparation (and irradiation), provided they are stored in
a blood storage refrigerator at 2 C 6 C.
3. Once erythrocytes have been made suitable for intra-uterine administration, the
component can no longer be stored and should be administered immediately.
42
43
Recommendations* 2.3.3
1.
2.
3.
4.
Platelet hyperconcentrate
Recommendation* 2.3.3
Platelet hyperconcentrate is supplied in a 20 mL syringe and can be kept (at room
temperature) for a maximum of 3 hours.
Platelets in 100% PAS II
Recommendation* 2.3.3
Once processed, platelets in 100% PAS II can be kept for 3 hours in a platelet storage bag, placed
in a platelet storage cupboard under continuous agitation at 20 24 C.
2.3.4 Storage conditions, shelf-life and transport of plasma
In order to maintain the activity of the clotting factors, this component should be stored at a
temperature of -25 C or lower. The shelf-life in that case is a maximum of two years. During
transportation, the component temperature should not exceed -18 C.
The plasma should be thawed in a designated and validated piece of equipment, such as a
special microwave oven, plasmatherm or in a waterbath, at a maximum of 37 C
(temperature monitoring is required).
A loss of activity of the clotting factors occurs upon thawing, which means that the storage
duration of the thawed component is limited. Dutch (Lamboo 2007) and foreign studies show
that the activity of ADAMTS13 did not decrease significantly for two weeks after thawing,
provided the plasma was stored at 2 C 6 C. Factor V and Factor VIII activity decreased
by 25 35% and 50% respectively. The fibrinogen level decreased by 8% (Buchta 2004,
Downes, 2001, Woodhams, 2001. According to the Guide to the preparation, use and
quality assurance of blood components, 13th ed from the Council of Europe, the plasma
44
component should contain > 70% of the activity of the fresh component after thawing
(Council of Europe 2007). This requirement is not met for the FVIII activity in the thawed
component that is stored at 2 C 6 C for 14 days. Nevertheless, we can conclude that this
component can be deemed suitable for adequate support of haemostasis following trauma
or massive blood loss, with the exception of FVIII deficient patients. Thawed plasma
components should preferably be administered as soon as possible, however the fact that
sufficient clotting factor activity is maintained means that the component can also be stored
at 2 C-6 C for at least 24 hours.
During the storage of thawed frozen plasma, the concentration of the lipophilic plasticiser in
the plastic bag the di(2-ethyl hexyl) phthalate (DEHP) increases in the plasma over time,
most significantly at room temperature and to a lesser extent at 4 C (Luban 2006). This
DEHP has toxic effects on fertility and the foetal development. (Commission Directive 2001,
(http://www.noharm.org/lib/downloads/pvc/DEHP_Exposure_of_Infants.pdf)).
Due to the lack of alternatives, the benefits of thawed plasma on the shelf for trauma
surgery (among others) must be weighed against the disadvantages of DEHP toxicity. It is
preferable to administer the plasma within two hours after thawing.
When stored at room temperature and after opening or inserting a needle/spike into the
system, the maximum storage time is limited to 6 hours due to the risks of bacterial growth.
During this period there is no significant difference in activity or level of clotting factors.
Plasma that has been thawed may not be frozen again.
Conclusions 2.3.4
Provided storage takes place at 2 C 6 C, the activity of ADAMTS13 in
plasma did not decrease significantly for 2 weeks after thawing. Factor V
and Factor VIII activity decreased by 25 35% and 50% respectively. The
Level 3
fibrinogen level decreased by 8%.
C
Level 3
Luban 2006
Recommendations 2.3.4
1.
2.
3.
4.
In order to maintain the activity of the clotting factors, plasma should be stored at a
temperature of -25 C or lower. The shelf-life in that case is two years.
During transportation, the temperature of the plasma should not exceed -18 C.
The plasma should be thawed in a designated and validated piece of equipment,
such as a special microwave oven, plasmatherm or in a waterbath, at a maximum of
37 C. Temperature monitoring is required.
It is recommended that thawed plasma components be administered as soon as
possible. However, the fact that sufficient clotting activity is maintained means that
the component can also be stored at 2 C 6 C for at least 24 hours.
45
5.
6.
When stored at room temperature and after opening or inserting a needle/spike into
the system, the maximum storage time is limited to 6 hours due to the risks of
bacterial growth.
Plasma that has been thawed may not be frozen again.
Maximum 3 days
Maximum 6 hours
Maximum 5 days
Maximum 24 hours
Maximum 28 days
Maximum 24 hours
Recommendation* 2.3.5
Please refer to table 2.3 Age of erythrocyte component at time of gamma irradiation and
shelf-life after gamma irradiation for the recommendations concerning the shelf-life of
gamma irradiated blood components .
2.3.6 Shelf-life of CMV negative / Parvo B19 safe components
Both specifications do not have any effect on the shelf-life, storage time or transport
conditions for the blood components.
46
Shelf-life of granulocytes
The granulocyte component has a short shelf-life, with infusion within 6 hours of collection
being preferable. The maximum shelf-life is 24 hours (Drewniak 2008, Hubel 2005).
Recommendation* 2.3.6
The granulocyte component has a short shelf-life, with infusion within 6 hours of collection
being preferable. The maximum shelf-life for granulocyte components is 24 hours.
2.4
Nursing aspects
2.4.1 Nursing aspects, general
Many practical matters concerning transfusions of blood components are based on habit and
experience, they are rarely evidence-based. Systematic research would be very desirable. In
addition to nurses, perfusionists and anaesthesiology assistants are the professionals who
perform the blood transfusion. These employees are the last link in the long transfusion
chain and they have specific responsibilities; they are subject to specific requirements.
Based on a number of frequently asked questions, the working group has formulated
recommendations* (opinion of the working group) based on international (UK, Australia)
guidelines and manuals (see literature list).
A number of these recommendations* apply mainly to transfusions in non-acute situations
on non-surgical wards. Peri-operative and/or acute blood loss sometimes requires deviation
from these recommendations.
Requirements for the nurse who administers a transfusion
Recommendations* 2.4.1
1.
The employee who performs the blood transfusion must be authorised and skilled, as
described in the BIG Law. Nurses must have a BIG registration for this and other
employees (anaesthesiology assistants, perfusionists) are deemed authorised and
skilled due to their training.
2.
It is essential that the nurse has access to clear procedures and is regularly involved in
the administration of blood components.
3.
It is recommended that nurses involved in blood transfusions be given regular training
concerning blood transfusion and the possible side effects.
Recommendations* 2.4.1
1.
2.
3.
The employee who administers the blood component is responsible for checking the
blood component, patient identification, information and the entire procedure
surrounding the administration.
The person who actually administers the transfusion is responsible for recording the
information in the (electronic) patient file and for reporting any transfusion reaction
according to the hospital protocol.
The Board of Directors, or an official (haemovigilance officer or blood transfusion
commission) appointed by the board, is responsible for the correct process when
reporting transfusion reactions to the various responsible institutions and for
recording the procedures within the institution.
47
48
4. The working group is of the opinion that the infusion pump or syringe pump and the
volume administered should preferably be checked at least 1x per hour during a
transfusion of a unit of erythrocytes.
Filters
A coarse filter (170 200 ) removes the minimal clots and precipitate that can form during
the preparation process of the blood component.
Recommendation* 2.4.2
Blood administration systems should be fitted with a coarse filter (170 200 filter)
Administration systems
Recommendations* 2.4.2
1.
2.
3.
Blest 2008
Recommendation 2.4.2
Administration systems for blood components should be replaced every 12 hours and as
soon as possible after the end of the administration.
The clean blood administration system should be filled with NaCl 0.9% before the
start of the transfusion in order to prevent the blood component from sticking to the
wall of the system as much as possible.
Should the administration system be rinsed with NaCl 0.9% after each blood
component?
There is no recent literature available about rinsing the administration system after each
blood transfusion. Glucose 5% can cause haemolysis and may never be used to fill and/or
rinse an administration system. Calcium-containing solutions interact with a citrate-
49
containing blood component and are therefore strongly discouraged. An isotonic calciumfree solution could be used, but it is safer to use NaCl 0.9% solution as the exact contents of
other solutions is usually not known.
Recommendation* 2.4.2
The working group is of the opinion that:
The blood administration system should be (visually) clean before the start of a
transfusion.
The blood administration system should be filled with NaCl 0.9% before the start of
the transfusion.
The blood administration system should be rinsed with NaCl 0.9% after each
transfusion episode.
Administration of platelets and erythrocytes via the same administration set
If platelets are administered via the same administration system that has previously been
used for erythrocytes, the precipitate in the filter from the first transfusion will trap the
platelets and hamper their administration. In practice, the administration of erythrocytes
after transfusion of platelets does not pose any problems.
Recommendation* 2.4.2
The working group is of the opinion that platelets should always be administered via a clean
(unused) administration system.
Warming of erythrocytes and/or plasma before administration
Recommendations* 2.4.2
1. The warming of erythrocytes and/or plasma before transfusion is recommended in the
following cases only:
for patients with clinically proven, strong cold antibodies, which have been
demonstrated in vitro at 37 C.
2. The warming of erythrocytes is performed exclusively upon prescription of the treating
doctor (following advice from the blood transfusion laboratory).
3. Erythrocytes and plasma should only be warmed in equipment validated specifically for
that purpose. Erythrocytes and plasma should never be warmed in a standard
microwave oven, in warm water or on a central heating radiator.
Administration speed of the various short shelf-life blood components in neonates, children
and adults
50
Recommendation* 2.4.2
The administration speeds as listed in table 2.4 are recommended for neonates, children and
adults:
Table 2.4: Administration speeds
erythrocytes
platelets
quarantine plasma
neonates
15 mL/kg
in 3 hours
10 15 mL/kg
maximum in 3 4
hours
children
10 15 mL/kg
in 3 4 hours
10 15 mL/kg
maximum in 3 4
hours
adults
1-61 hours/unit
20 minutes
20 30 minutes
: If the infusion speed needs to be so low that the entire unit cannot be administered within
6 hours, this could form a reason to transfuse smaller quantities (paediatric units).
Other considerations
Slow administration and the possible use of a diuretic are advised for cardiac-compromised
patients (see Recommendation 4 under 7.2.7).
51
52
Recommendations* 2.4.2
1. The patient should be observed for the first 5 to 10 minutes of the transfusion.
2. It is recommended that no more than 20 mL of the blood component be administered
during the first 10 minutes of the transfusion. If no abnormalities are observed, the
transfusion can then be continued at the agreed administration speed.
3. Please refer to table 2.5 for the vital parameters that should be recorded before, during
and after blood transfusion.
temperature
15 during
during
transfusion
minutes
transfusion
disconnection
after start of reaction
transfusion
+
+
+
+
heart rate
blood
pressure
evaluate
condition
of patient
recording
of
administration
recording
presence/
absence
of
transfusion
reaction
after
transfusion
+
+
+
53
Recommendation* 2.4.2
One should wait at least 15 minutes after an erythrocyte transfusion to determine the effect
of the transfusion.
The simultaneous administration of blood components with intravenous medications through
a single lumen infusionsystem
Due to the possible occurrence of a reaction between the medicine and the bloodcomponent
it is not recommended to administer blood components simultaneously with intravenous
medication solutions through a single lumen infusion system. Undesirable immediate effects
such as haemolysis and/or agglutination depend among other factors on the type of blood
component , dosage of the medication and the duration of the contact between the two (van
den Bos 2003). This and other studies show that the extent of haemolysis as a result of the
simultaneous administration in the conditions examined is acceptable. However, it is
difficult to extrapolate in vitro study results to clinical relevance (Murdock 2009). Further
research on this subject is desirable.
Other considerations
The recommendation that medication and a blood component may not be administered
simultaneously via a single lumen infusion system regularly causes practical problems.
Further research on this subject is desirable.
Recommendations* 2.4.2
1. Medication may never be administered simultaneously with blood components via a
single lumen infusion system.
2. Medication can only be administered via a single lumen infusion system if a second
administration system with a three-way stop cock is used whilst the administration of the
blood component is halted temporarily.
3. The infusion system (peripheral infusion) must be rinsed thoroughly before and after the
administration of medication using an indifferent infusion solution such as NaCl 0.9%,
before the transfusion can resume.
4. The transfusion may not be interrupted for longer than 2 hours and the transfusion line
may never be disconnected in the meantime due to the risk of bacterial contamination.
5. In general, double or triple lumen catheters are suitable for the simultaneous
administration of blood components and medication. It is advisable to reserve one lumen
specifically for the administration of blood components .
6. Further research into the effect of the simultaneous administration of blood components
and intravenous medication through a single lumen infusion system is recommended.
Literature 2.1
1.
2.
54
Blumberg N, Heal JM. ABO-mismatched platelet transfusions and clinical outcomes after
cardiac surgery. Transfusion. 2002 Nov;42(11):1527-8; author reply 1528-9. Comment on:
Transfusion. 2002 Feb;42(2):166-72.
De Wildt-Eggen J, Nauta S, Schrijver JG, van Marwijk Kooy M, Bins M, van Prooijen.
Reactions and platelet increments after transfusion of platelet concentrates in plasma or an
additive solution: a prospective, randomized study. Transfusion. 2000 Apr; 40(4):398-403.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Guide to the preparation, use and quality assurance of blood components,13 th edition.
Council of EuropePublishung.ISBN-10:92-871-6137-2.
Harris SB, Josephson CD, Kost CB, Hillyer CD. Nonfatal intravascular hemolysis in a
pediatric patient after transfusion of a platelet unit with high-titer anti-A. Transfusion. 2007
Aug;47(8):1412-7.
International Forum, Vox Sang. 2005;88:207-21 Transfusion of apheresis platelets and ABO
groups.
Kerkhoffs JL, Eikenboom JC, Schipperus MS, van Wordragen-Vlaswinkel RJ, Brand R,
Harvey MS, de Vries RR, Barge R, van Rhenen DJ, Brand A. A multicenter randomized study
of the efficacy of transfusions with platelets stored in platelet additive solution II versus
plasma. Blood. 2006 Nov 1;108(9):3210-5. Epub 2006 Jul 6.
Lin Y, Callum JL, Coovadia AS, Murphy PM. Transfusion of ABO-nonidentical platelets is not
associated with adverse clinical outcomes in cardiovascular surgery patients. Transfusion.
2002 Feb;42(2):166-72.
Mair B, Benson K. Evaluation of changes in hemoglobin levels associated with ABOincompatible plasma in apheresis platelets. Transfusion. 1998 Jan;38(1):51-5.
Nadine Shehata, Alan Tinmouth, Gary Naglie, John Freedman, and Kumanan Wilson, ABOidentical versus nonidentical platelet transfusion: a systematic review.Transfusion 2009, 49
(11), 2442-2453
Sanquin Bloedwijzer 2009, KD00.001.F.SQ/003-2009
Sanquin Richtlijn Bloedproducten 2008.
Transfusiegids 2007 LUMC/EMC/Sanquin Bloedbank regio ZW.
Van Rhenen DJ, Gulliksson H, Cazenave JP, Pamphilon D, Davis K, Flament J, Corash
Therapeutic efficacy of pooled buffy-coat platelet components prepared and stored with a
platelet additive solution. Transfus Med. 2004 Aug;14(4):289-95.
Literature 2.2
1.
2.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Adler SP. Data that suggest that FFP does not transmit CMV. Transfusion 1988;28:604.
Atallah E, Schiffer CA. Granulocyte transfusion. Current Opinion in Hematology 2005;134549. Bone Marrow Transplant 2008;42:679-684.
Bowden RA et al. A comparison of filtered elukocyte-reduces and cytomegalovirus (CMV)
seronegative blood products for the prevention of transfusion-associated CMV infection after
marrow transplant. Blood 1995;86:3598-603.
De Waal KA, Baerts W, Offringa M. Systematic review of the optimal fluid for dilutional
exchange transfusion in neonatal polycythaemia. Arch Dis Child Fetal Neonatal Ed.
2006;91:F7-10.
Graham AS et al. Revisisting the use of granulocyte transfusions in pediatric oncology
patients. J. Handbook of transfusion medicine. UK Blood Services 4th ed. McClelland editor.
London TSO 2007.
James DJ et al. The presence of free infectious cytomegalovirus (CMV) in the plasma of
donated CMV-seropositive blood and platelets. Transfus Med 1997;123:123-6.
Khn JE. Transfusion-associated infections with cytomegalovirus and other human
herpesviruses. Infus Ther Transfus Med 2002;27:138-43.
Laupacis A et al. Prevention of post-transfusion CMV in the era of universal WBC reduction: a
consensus statement. Review. Transfusion 2001;41:560-9.
Massey E et al. Granulocyte transfusions for preventing infections in patients with neutropenia
or neutrophil dysfunction. Cochrane Database Syst. Rev. 2009 21:CD0005341
Munks R et al. A comprehensive IgA service provided by a blood transfusion service.
Immunohematology 1998;14:155-60.
Pediatr. Hematol. Oncol 2009 31;:161-165
Preiksatis JK. The cytomegalovirus-safeblood product: is leukoreduction equivalent to
antibody screening? Transfus Med Rev 2000; 14:112-36.
Price TH. Granulocyte transfusion: current status. Seminars in Hematology 2007;44:15-23.
55
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Roback JD et al. Longitudinal monitorin of WBC subsets in packed RBC units after filtration:
implications for transfusion transmission of infections. Transfusion 2000;40:500-6.
Sachs UJ et al. Safety and efficacy of therapeutic early onset granulocyte transfusions in
pediatric patients with neutropenia and severe infections. Transfusion 2006; 46: 19091914.
Salama et al. Rapid detection of antibodies to immunoglobulin A molecules by using the
particle immunoassay. Vox Sang 2001;81:45-48.
Sandler SS and Zantek ND. Review: IgA anaphylactic transfusion reactions. Part II. Clinical
diagnosis and bedside management. Immunohematology 2004;20:234-238
Sanquin Bloedwijzer 2009, KD00.001.F.SQ/003-2009
Sanquin Richtlijn Bloedproducten 2008
Seidel MG et al.Randomized phase III study of granulocyte transfusions in neutropenic
patients.
SHOT annual report 2006 ( www.shotuk.org)
Signalement Bloedproducten en Parvovirus B19Gezondheidsraad 2002, publicatie nr.
2002/07.
Smith KL et al. Removal of cytomegalovirus DNA from donor blood by filtration. Br J Haematol
1993;83:640-2.
Stanworth SJ et al. Granulocyte transfusions for treating infections in patients with neutropenia
or neutrophil dysfunction. Cochrane Database of Systematic Reviews 2005; 20 May 2005.
Transfusiegids 2007 LUMC/EMC/Sanquin Bloedbank regio ZW
transplantation in pediatric patients with chronic infections. Bone Marrow Transplantation
2006;37:331-333.
Vassallo RR. Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis,
incidence,a nd supply of IgA deficint products. Immunohematology 2004;20:226-233.
Wetering van de MD et al. Granulocyte transfusions in neutropenic children: a systematic
review of the literature. European Journal of Cancer 2007;43:2082-2092.
Richtlijn Hyperbilirubinemie, http://www.cbo.nl/thema/Richtlijnen/Overzichtrichtlijnen/Kindergeneeskunde/). (NVK, 2008).
Gezondheidsraad Bloedproducten en Parvovirus B19, publicatie nr 2002/07 )
Literature 2.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
56
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
Kneyber MC et al. Length of storage of red blood cells does not affect outcome in critically ill
children. Intensive Care Med. 2009 Jan;35(1):179-80.
Koch CG et al. Duration of red-cell storage and complications after cardiac surgery.
N.Engl.J.Med. 2008 Mar 20;358(12):1229-39.
Koch CG. NCT00458783: Red Cell Storage Duration and Outcomes in Cardiac Surgery.
Ongoing study.
Lacroix J. ISRCTN44878718: Age of BLood Evaluation (ABLE) trial in the resuscitation of
critically ill patients. Ongoing study.
Lamboo M, Poland DC, Eikenboom JC, Harvey MS, Groot E, Brand A, de Vries RR. Transfus
Med. 2007;17:182-6. Coagulation parameters of thawed fresh-frozen plasma during storage
at different temperatures.
Leal-Noval SR et al. Impact of age of transfused blood on cerebral oxygenation in male
patients with severe traumatic brain injury. Crit Care Med. 2008 Apr;36(4):1290-6.
Leal-Noval SR et al. Influence of erythrocyte concentrate storage time on postsurgical
morbidity in cardiac surgery patients. Anesthesiology 2003 Apr;98(4):815-22.
Martin CM et al. Age of transfused red blood cells is associated with ICU length of stay. Clin
Invest Med 1994;17:124.
Moreira OC, Oliveira VH, Benedicto LB, Nogueira CM, Mignaco JA, Fontes CF, Barbosa LA.
Effects of gamma-irradiation on the membrane ATPases of human erythrocytes from
transfusional blood concentrates. Ann Hematol. 2008;87:113-9.
Murrell Z et al. The effect of older blood on mortality, need for ICU care, and the length of ICU
stay after major trauma. Am.Surg. 2005 Sep;71(9):781-5.
Offner PJ et al. Increased rate of infection associated with transfusion of old blood after
severe injury. Arch.Surg. 2002;137:711-6.
Purdy FR et al. Association of mortality with age of blood transfused in septic ICU patients.
Can.J.Anaesth. 1997;44:1256-61.
Relevy H, Koshkaryev A, Manny N, Yedgar S, Barshtein G. Transfusion 2008;48:136-46.
Blood banking-induced alteration of red blood cell flow properties.
Sanquin Bloedwijzer 2009, KD00.001.F.SQ/003-2009
Sanquin Richtlijn Bloedproducten 2008
Transfusiegids 2007 LUMC/EMC/Sanquin Bloedbank regio ZW
Vamvakas EC et al. Length of storage of transfused red cells and postoperative morbidity in
patients undergoing coronary artery bypass graft surgery. Transfusion 2000;40(1):101-109.
Vamvakas EC, Carven JH. Transfusion and postoperative pneumonia in coronary artery
bypass graft surgery: effect of the length of storage of transfused red cells. Transfusion
1999;39(7):701-10.
Vamvakas.Transfusion 2010;59: 600-610
Van de Watering L et al. Effects of storage time of red blood cell transfusions on the
prognosis of coronary artery bypass graft patients. Transfusion 2006 Oct;46(10):1712-8.
Van der Meer PF, Gulliksson H, Aubuchon JP, Prowse C, Richter E, de Wildt-Eggen J;
Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Vox Sang. 2005;88:22734. Interruption of agitation of platelet concentrates: effects on in vitro parameters.
Van der Meer PF, Liefting LA, Pietersz RN. Transfusion. 2007;47:955-9. The effect of
interruption of agitation on in vitro measures of platelet concentrates in additive solution.
Von Heymann C, Pruss A, Sander M, Finkeldey A, Ziemer S, Kalus U, Kiesewetter H, Salama
A, Spies C. Anesth Analg. 2006;103:969-74. Thawing procedures and the time course of
clotting factor activity in fresh-frozen plasma: a controlled laboratory investigation.
Wagner SJ, Myrup AC. Transfus Med. 2006;16:261-5. Prestorage leucoreduction improves
several in vitro red cell storage parameters following gamma irradiation.
Weinberg JA et al. Age of transfused blood: an independent predictor of mortality despite
universal leukoreduction. J.Trauma 2008 Aug;65(2):279-82.
Yap CH et al. Age of transfused red cells and early outcomes after cardiac surgery.
Ann.Thorac.Surg. 2008 Aug;86(2):554-9.
Zallen G et al. Age of transfused blood is an independent risk factor for postinjury multiple
organ failure. Am.J.Surg. 1999;178:570-2.
57
38.
39.
40.
41.
42.
43.
Buchta, C., Felfernig, M., Hocker, P., Macher, M.,Kormoczi, G.F., Quehenberger, P., Heinzl,
H. & Knobl, P. (2004) Stability of coagulation factors in thawed, solvent/detergent-treated
plasma during storage at 4 degrees C for 6 days. Vox Sanguinis, 87, 182186.
Downes, K.A., Wilson, E., Yomtovian, R. & Sarode, R.(2001) Serial measurement of clotting
factors in thawed plasma stored for 5 days. Transfusion, 41, 570.
Woodhams, B., Girardot, O., Blanco, M.J., Colesse, G. & Gourmelin, Y. (2001) Stability of
coagulation proteins in frozen plasma. Blood Coagulation and Fibrinolysis, 12, 229236.
Commission Directive 2001/59/EC.
www.noharm.org/pvcDehp
Guide to the preparation, use and quality assurance of blood components; Council of Europe
Publishing 13th edition ( ISBN 978-92-871-6137-6)
Literature 2.4
1.
2.
3.
4.
5.
6.
7.
8.
9.
20.
21.
58
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
ADDENDUM
Bloodcomponents : characteristics, indications, logistics and
administration
Table 2.6: Translation table component names
CBO Guideline
Erythrocytes
Alternative name
Sanquin Blood Guide
Erythrocyte concentrate Erythrocytes in SAGM
(EC)
Irradiated erythrocytes
Washed erythrocytes
Apheresis platelets
Plasma
Quarantine plasma
FFP (fresh frozen
plasma)
tariff
210,50
508,60
181,00
59
3.1
Accessory conditions for processing of requests for blood and blood
components
Scientific support
The developments in clinical chemistry and haematology laboratories over the past decades
with both the number of requests and the complexity of the examination requested
increasing means that high standards apply to correct administrative processing and the
associated logistics processes. This applies in particular to all transfusion-related requests
for examination and release of blood components . Linden, Williamson, Love and Stainsby
analysed the blood transfusion incidents that were reported in the state of New York from
1990 to 2000 (Linden 2000, Linden 1992) and similar reports in England from the British
Haemovigilance Service SHOT (Williamson 1999), from 1996 to 2000 (Love 2001) and from
1996 to 2003 (Stainsby 2005). These analyses show that over 50% of the reported incidents
were caused by administrative errors 1. Of these administrative errors, 10 50% were due to
collection for the wrong patient or incorrect identification of the blood sample.
Dzik et al showed in 2003 in an international study in 10 countries of 700,000 samples for
transfusion laboratories that for 1:2000 samples the blood group did not match a previous
determination (Dzik 2003). This was confirmed by Murphy et al in 2004 (Murphy 2004).
The reports from the TRIP National Haemovigilance Office from 2003 through till 2007 show
that for the total of 317 reported near-accidents, more than 50% were caused by
identification errors in sample or patient. Of the wrongly administered blood components in
that period, 29% was destined for a different patient. The TRIP reports also show that 15%
of the wrong components were not irradiated by mistake (TRIP 2003 through 2009). This
corresponds to the analyses by Love et al (Love 2001).
1
Conclusions 3.1
Incorrectly identified blood samples are an important source of errors in
blood transfusion incidents.
Level 3
C
60
TRIP reports 2003 through 2009, Stainsby 2005, Murphy 2004, Dzik
2003, Love 2001, Williamson 1999, Linden 1992
Level 3
Other considerations
Upon receipt of blood samples and/or transfusion requests, the blood transfusion laboratory
has a verifying role. Upon receipt, they check whether the request and/or the blood sample
meet the criteria set and demanded by the institution.
The procedures set out for this stipulate at least the following points:
unambiguous identification of the blood sample and the patient is guaranteed. This means
that tubes of blood are labelled in the presence of the patient. These labels contain
immediately legible information and at least two characteristics that are unique and can be
traced independently to the patient, namely the full name, date of birth and/or social security
number or another unique number from a patient identification system. In addition to
immediately legible information, it is preferable to use barcodes and/or RFIDs (radio
frequency identification) .
If the patient identification and the linking of patient identification to the blood sample always
occurred correctly, in theory only one collection would suffice for the definitive determination
of the ABO/RhD blood group. However, in practice, the state-of-the-art procedure is to
determine ABO/RhD blood group definitively using two independent blood collections in
order to trace any errors in the identification process. This often leads to discussions about
organisational and logistical matters. Each collection is determined by the three Ws: who
(phlebotomist), where (outpatient department or inpatient ward) and when (date/time). In this
context independently means that at least one of the three Ws differs during the two
collections with complete patient identification. The blood transfusion laboratory cannot
perform the compatibility study if the transfusion request does not meet the criteria set by the
institution. This includes that the ABO/RhD blood group must be determined using two blood
samples, with an unambiguous link between the sample and the patient.
The requesting doctor is responsible for the correct component selection. In
consultation with the treating doctor, the blood transfusion laboratory records in the
transfusion database whether there is an indication for specific blood components
and the time-frame that applies to these components for example, irradiated blood
components and checks that the request conforms to these requirements. In such
an event, the blood transfusion laboratory can use the transfusion database, as
recorded in the own written and/or digital blood transfusion database, to check
whether the requested component matches the historical information, such as typed,
irradiated, washed et cetera. The patients antibody history is consulted with each
request for a cellular blood component and also TRIX for every new treatment
(period).
The name and date of birth and/or identification number of the patient (identified
according to an emergency procedure if necessary) and the name of the requesting
doctor are recorded.
In order to prevent unnecessary time loss in case of cito requests, everyone who is
involved in the transfusion chain must be familiar with a clear and workable cito
procedure.
Blood Transfusion Guideline, 2011
61
Due to the frequency at which administrative errors play a role in among others
the transfusion of ABO incompatible units, thorough documentation of the procedures
surrounding the determination of the blood group and strict adherence to these
procedures is essential. The number of manual administrative procedures should be
kept to a minimum.
Recommendations 3.1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
62
The blood transfusion laboratory only accepts samples that have a label that
unambiguously links the tube to the patient. This means that tubes of blood are
labelled in the presence of the patient. These labels contain immediately legible
information and at least two characteristics that are unique and can be traced
independently to the patient, namely the full name, date of birth and/or social security
number or another unique number from a patient identification system. In addition to
immediately legible information, it is preferable to use barcodes and/or RFIDs (radio
frequency identification).
Upon receipt of blood samples and/or transfusion requests, the blood transfusion
laboratory has a verifying role. The blood transfusion laboratory only accepts
requests for transfusion if the identification of the patient on the request is identical to
that of the blood sample. Differences, however small, due to writing errors should be
verified.
At least two independent collections of blood samples must be performed for the
definitive determination of the ABO/RhD blood group. Independent means that the
two collections with complete patient identification must be performed at different
times, different locations or by different phlebotomists. For both samples there must
be an unambiguous identification of the patient and an unambiguous link between the
sample and the patient. An ABO/RhD blood group is only definitively determined if
this requirement has been met without the discovery of any discrepancies.
If there is any doubt, a new sample should always be collected and the ABO/RhD
blood group determination should be repeated. Based on the outcome of a careful
analysis of all available data, the blood transfusion laboratory can consider the result
from this sample as a first or second blood group determination.
The cause of discrepancies between ABO/RhD blood group determinations should
always be examined.
The blood transfusion laboratory will not process any transfusion requests that do not
meet the criteria set by the institution. This includes that the ABO/RhD blood group
must be determined using two blood samples, with an unambiguous link between the
sample and the patient.
The requesting doctor should supply relevant clinical information (about antibodies
(allo and/or auto), pregnancies, transplants, haemoglobinopathies, etc.) to the
transfusion laboratory.
The requesting doctor is responsible for the choice of blood component .
All care providers involved in the transfusion chain must be familiar with a clear and
workable cito procedure.
In consultaiton with the treating doctor, the blood transfusion laboratory records in the
transfusion database whether there is an indication for specific blood components
and the time-frame that applies to these components and checks that the request
conforms to these requirements.
Blood Transfusion Guideline, 2011
11.
12.
13.
3.2
In the case of a request by telephone, at least the name and date of birth and/or
identification number of the patient (identified according to an emergency procedure
if necessary) and the name of the requesting doctor are recorded.
The patients antibody history must be consulted with each request for a cellular
blood component and TRIX should also be consulted for each new treatment
(episode) (see chapter 3.3.3 and chapter 7.2.2).
Due to the frequency at which administrative errors play a role in among others
the transfusion of ABO incompatible units, thorough documentation of the procedures
surrounding the determination of the blood group and strict adherence to these
procedures is essential. The number of manual administrative procedures should be
kept to a minimum.
Laboratory examinations
63
Level 3
Level 3
Level 3
Sazama 1990
The ABO blood group system is the most important blood group system for
transfusions and an ABO blood group determination should therefore meet
the highest quality requirements. This includes that the ABO blood group
determination should be performed in its entirety. This means that the
presence or absence of the antigens of the ABO system on the
erythrocytes of the patient should be determined using test reagents and
the presence or absence of anti-A and anti-B antibodies in the
plasma/serum of the patient should be determined using test erythrocytes.
D
C
Recommendations 3.2.1
1.
For adults and children older than three months, the ABO blood group determination
should be performed in its entirety. This means that the presence or absence of the
antigens of the ABO system on the erythrocytes of the patient should be determined
using test reagents and the presence or absence of anti-A and anti-B antibodies in
the plasma/serum of the patients should be determined using test erythrocytes.
2.
See also paragraph 3.1, recommendations 1 through 5.
ABO blood group determination in children up to the age of three months
The ABO blood group antigen determination usually cannot be confirmed in neonates and
children up to the age of three months, due to the presence/absence of the corresponding
antibodies anti-A and/or anti-B. The agglutinating IgM antibodies often can only be
demonstrated from three months after birth. Any IgG antibodies that are present are usually
from the mother. The number of A and/or B antigens in neonates is a factor 2 to 3 lower than
in adults (Klein 2005, BCSH 2004, SBBTS 2009, Daniels 1995).
Conclusion 3.2.1
Level 3
64
Other considerations
Due to the above-mentioned facts, an ABO/RhD blood group determined from two
independent samples from a neonate is preliminary in nature until the ABO blood group has
become definitive, but it may be used for the selection of ABO/RhD identical blood
components.
In the case of cord blood, it is important to rule out a false positive result due to the
Whartons jelly that can cause pseudo-agglutination.
Due to the frequency at which administrative errors play a role in among others the
transfusion of ABO incompatible units, thorough documentation of the procedures
surrounding the determination of the blood group and strict adherence to these procedures
is essential. The number of manual administrative procedures should be kept to a minimum.
Comment: If clinical circumstances such as prematurity, dysmaturity or low birth
weight hamper a blood collection from the child in order to perform a second
ABO/RhD determination, the required second blood group determination can be
omitted. The child may then only receive transfusions of O- erythrocyte concentrate.
Recommendations 3.2.1
1. In neonates and children up to the age of three months after birth, the determination of A
and B antigens will suffice for the ABO blood group determination. For cord blood, a
false positive result due to the Whartons jelly must be ruled out.
2.
The registration of the ABO blood group in neonates and children up to the age of
three months after birth is preliminary in nature, until the ABO blood group has
become definitive.
3.
This preliminary ABO blood group can be used for identical transfusion of blood
components.
4.
See also paragraph 3.1, recommendations 1 through 5.
3.2.2 Rhesus D blood group determination
Scientific support
After the ABO blood group system, the rhesus blood group system and particularly the
Rhesus D antigen (RhD) is the most important blood group system in transfusion practice
(Issit 1998, Daniels 1995). This is because the RhD blood group is very immunogenic
(Gonzales-Porras 2008, Klein 2005), antibodies against RhD can cause haemolytic
transfusion reactions and during pregnancy it can be responsible for haemolytic disease in
the foetus and neonate. For the transfusion practice it is therefore important to prevent RhD
negative patients (recipients) being typed as RhD positive.
The number of RhD antigens on the erythrocyte membrane can vary significantly from
person to person (Daniels 1995). The most well-known quantitative RhD antigen abnormality
is the weak RhD antigen. Patients with a weakened (low number) but completely intact RhD
antigen are RhD positive and unable to produce alloantibodies against the RhD antigen. In
addition to quantitative variations, a large number of qualitative variants of the RhD antigen
have also been described. Patients with an RhD variant (incomplete RhD antigen) can form
65
allo-anti RhD antibodies against the epitopes of the RhD antigen that they do not possess
(Klein 2005). The most frequently occurring RhD variant is RhD class VI with an incidence of
1:5,000 to 1:6,800 (Caucasian population). This is also the only RhD variant for which it has
been described that an alloantibody against the missing part of the RhD has caused
haemolytic disease of the newborn. Most of the other RhD variants are much rarer
(<1:60,000) in the Caucasian population (Flegel 1996).
Immunisation can occur during pregnancy because foetal erythrocytes enter the mothers
circulation. The IgG antibodies formed in this manner can then cross the placental barrier
and cause breakdown of the foetal erythrocytes. In severe cases, this can result in
haemolytic disease of the foetus and newborn (Klein 2005). Since 1969 in the Netherlands,
in order to prevent RhD immunisation, anti-RhD immunoglobulin has been administered
prophylactically to RhD negative women who give birth to an RhD positive child. Therefore,
when determining the RhD blood group in neonates, both the weak RhD antigens and RhD
variants are detected and this determination therefore differs from the RhD determination for
patients.
Conclusions 3.2.2
Level 3
Level 3
Level 3
Daniels 1995
Jones 2004
Other considerations
Tracing of very weak RhD antigens in blood recipients is not clinically relevant: if a recipient
has in an exceptional case incorrectly been typed as RhD negative, then RhD negative
blood will be administered, which will have no negative consequences for the patient. The
tracing of very weak RhD antigens in pregnant women also has no clinical importance. In
rare cases the recipient could erroneously be typed as RhD negative and will then
unnecessarily be administered anti-RhD immunoglobulin. This will not result in clinical
problems.
Tracing of very weak RhD antigens using the anti-globulin test in recipients of blood is
strongly discouraged. If there are sensitised (IgG coated) erythrocytes present (positive
66
direct anti-globulin test (DAT)) one might erroneously conclude that the recipient is RhD
positive. A recipient with an RhD variant antigen that is determined to be D positive runs the
risk during transfusion of an RhD positive erythrocyte concentrate of forming antibodies
against the parts of the RhD antigen that he/she is lacking. The chance of this (and an
additional chance of haemolytic disease of the foetus and newborn) is mainly present in
recipients with a RhD-VI variant. Due to the frequency at which the RhD-VI variant occurs it
is important to take this into consideration when selecting the reagents. This does not apply
to the other RhD variants.
The sensitive RhD determination in the anti-globulin test causes false positive results in
people who have in vivo bound antibodies on the erythrocytes (DAT).
Due to the frequency at which administrative errors play a role in blood transfusions,
thorough documentation of the procedures surrounding the determination of the RhD blood
group and strict adherence to these procedures is essential. The number of manual
administrative procedures should be kept to a minimum.
Recommendations 3.2.2
1.
Due to the chance of anti-RhD formation and future haemolytic transfusion reactions,
it should be prevented that patients who are RhD negative are erroneously labelled
RhD positive.
2.
For the RhD blood group determination, the hospital should distinguish between two
groups, namely: recipients of blood and neonates (due to the administration of antiRhD immunoglobulin to the mother).
3.
For the determination of the RhD blood group in recipients of blood, the use of one
anti-RhD reagent will suffice, provided the RhD-VI variant has been shown to be RhD
negative.
4.
Due to the administration of anti-RhD immunoglobulin to the mother, the
determination of the RhD blood group in neonates should use anti-RhD reagents that
show RhD-VI variant and weak RhD antigens to be RhD positive.
5.
If the neonate is the recipient of a blood component, the use of one anti-RhD reagent
will suffice, see also recommendation 3 above.
6.
For the RhD determination in recipients of blood, it is not recommended to expand
the test with an anti-globulin phase if the anti-RhD reagent produces a negative
reaction.
3.2.3 Actions in case of ABO blood group discrepancies
Scientific support
We can distinguish two types of discrepancies with the ABO blood typing: (1) the ABO blood
group does not match a previously determined blood group in the patient (Stainsby 2005,
Schulman 2001), or (2) there are discrepancies in the results of the blood group
determination itself (the results of the antigen determination on the erythrocytes does not
match the ABO antibodies found in the serum) (Brown 2005).
The most important causes for the occurrence of ABO blood group discrepancies in the first
group are administrative errors. Errors in the identification of the patient or the blood sample
occurred in 0.05% and 0.09% respectively of all blood collections (Dzik 2003, IGZ 2001,
Ibojie 2000, Linden 2000). In addition, errors can also occur in the processing of blood
67
samples, the reading or data entry of results, the selection or release of the blood
component and the administration to the (correct) patient (Schulman 2001, Baele 1994,
Linden 1992, Sazama 1990). Patients who have undergone an allogeneic bone marrow
transplantation form a particular risk group, because their original blood group has changed
(Brown 2005).
The actions to be taken in the case of ABO discrepancies are determined at the time that the
error is discovered. Data from the TRIP database for the period 2003 through 2007 show
that for the transfusion reactions (8683) that were reported, approximately 3% were the
result of the administration of an incorrect blood component (272) (TRIP 2003 through
2007).
Due to the small number of incidents in the Netherlands and the resulting lack of statistical
proof, the results of the British SHOT programme were also examined (Love 2001). The data
from the SHOT programme differs markedly from the Dutch data, partly due to a different
definition of incorrect blood component transfusion (IBCT). Rough risk estimates can be
made from the cumulative SHOT reporting over eight years. The percentage of IBCT is
approximately 70% of all reports. Of these IBCT, approximately 14% are due to an ABO
incompatible transfusion. Based on calculations using the SHOT figures, the risk of an IBCT
is approximately 1:15,000 transfused units and the risk of an ABO incompatible transfusion
is approximately 1:100,000 (Stainsby 2006, 2005).
Conclusions 3.2.3
Transfusion with ABO incompatible blood is usually the result of
administrative errors.
Level 3
C
Level 3
In addition, errors can also occur in the processing of blood samples, the
reading or data entry of results, the selection or release of the blood
component and the administration to the (correct) patient.
C
Errors in the identification of the patient or the blood sample occur in 0.05%
and 0.09% respectively of all blood collections.
Level 3
C
Dzik 2003, IGZ (Healthcare Inspectorate) report 2001, Ibojie 2000,
Linden 2000
Level 3
68
Level 3
Level 3
The data from the British SHOT programme differs markedly from the
Dutch data, partly due to a different definition of incorrect blood
component transfusion (IBCT). Rough risk estimates can be made from
the cumulative SHOT reporting over eight years: the risk of an IBCT is
approximately 1:15,000/transfused units and the risk of an ABO
incompatible transfusion is approximately 1:100.000.
C
Level 4
Brown 2005
Only considering the ABO blood group as definitive once it has been
confirmed using two samples collected independently of each other
without any discrepancies detected can reduce the risk of an incorrect
ABO blood group determination to a minimum.
D
Other considerations
Due to the frequency with which administrative errors play a role in among others the
transfusion of ABO incompatible units, thorough documentation of the procedures
surrounding the determination of the blood group and strict adherence to these procedures
is essential. The number of manual administrative procedures should be kept to a minimum.
If any discrepancies are discovered, one must examine whether this is due to a sample
mix-up or a patient mix-up. Depending on this analysis, the follow-up examination should
take place in accordance with the protocol that applies for the institution.
Recommendations 3.2.3
1.
2.
If any ABO discrepancies are discovered, one must examine whether this is a case
of sample mix-up or a patient mix-up. Depending on this analysis, the follow-up
examination should take place in accordance with the protocol that applies for the
institution.
Due to the frequency at which administrative errors play a role in among others
the transfusion of ABO incompatible units, thorough documentation of the procedures
surrounding the determination of the blood group and strict adherence to these
procedures is essential. The number of manual administrative procedures should be
kept to a minimum.
69
3.3
Level 4
Recommendations 3.3.1
1.
3.
70
2.
: ruling out anti-k (anti-Cellano) using homozygous test erythrocytes, change compared to
2004 version
3.3.1.2 Validity of antibody screening
Scientific support
Antibody formation usually takes place within three months of a transfusion or pregnancy.
However, a secondary immunisation can take place quickly (Shulman 1990). Based on data
from the literature and taking into consideration the increased sensitivity of the test systems,
there is general consensus that the period between antibody screening and transfusion
should be no more than 72 hours, because antibodies can be demonstrated within this
period.
If the patient has not had a transfusion or pregnancy in the past three months, then the
antibody screening is (as a general rule) valid until the next blood transfusion, provided the
anamnesis is absolutely reliable. If a cross match is performed for the patient in the IAT, the
same terms of validity apply to the cross match (Schonewille 2006, Schonewille 2006,
Redman 1996, Shulman 1990).
Conclusion 3.3.1.2
Level 3
Recommendations 3.3.1.2
1.
The maximum time between antibody screening and blood transfusion should be 72
hours.
2.
After transfusion or pregnancy, an antibody screening and cross match in the indirect
anti-globulin test is valid for a maximum of 72 hours after collection of the sample for
up to three months after the event.
3.
If one is absolutely certain that there has been no transfusion or pregnancy during
the past three months, then the antibody screening (as a general rule) is valid until
the next blood transfusion.
3.3.2 Compatibility study
Compatibility study according to the Type & Screen strategy
A compatibility study according to the Type & Screen strategy tests the ABO compatibility
between donor and patient. The antibody screening should be valid and negative
(Williamson 1999, Heddle 1992, Shulman 1990).
If the Type & Screen strategy is used, then the following requirements must be met:
The ABO blood group and the RhD antigen for both the patient and the donor(s)
must be definitively confirmed (see 3.2.1).
Screening for irregular erythrocyte antibodies in the patient using a three cell panel of
test erythrocytes must be negative.
Blood Transfusion Guideline, 2011
71
Checking the compatibility of the ABO blood group of the patient and the donor must
be part of the release procedure (AABB 2008).
Scientific support
American research shows that the chance of missing an antibody with the use of T&S
instead of an indirect antiglobulin test (IAT) cross match is approximately 1:5,500 per sample
or 1:10,000 per cross match (Garratty 2003). The risk of a severe haemolytic transfusion
reaction is 1:260.000 cross matches (Shulman 1990). Antibodies such as anti-Jka, anti-C,
anti-c, anti-Wra and anti-Kpa cannot be demonstrated with the screening, which means that
the chance of AHTR due to antibodies against low frequency antigens is estimated at
1:650,000 cross matches (Shulman 1984). As the occurrence of the low frequency antigens
can differ according to race and geographical location, research was performed on the Dutch
population in the period before and after the introduction of T&S. In this study by Schonewille
of 1795 patients with 2257 erythrocyte transfusions, the risk of an incompatible transfusion
due to antibodies against low frequency antigens was 1:204,000 and no transfusion
reactions due to antibodies against low frequency antigens were observed (Schonewille
2003).
As ABO incompatibility can cause a direct acute haemolytic transfusion reaction with fatal
consequences (Issit 1998), the ABO compatibility between donor and patient is of critical
importance. The hospital is responsible for the compatibility between donor and patient,
including the release of compatible blood components (IGZ 2001). The blood bank is
responsible for the contents of the component, in accordance with the label.
Conclusions 3.3.2
Level 3
American research shows that the chance of missing an antibody with the
use of T&S instead of an indirect antiglobulin test (IAT) cross match is
approximately 1:5,500 per sample or 1:10,000 per cross match.
C
Level 3
Further research into the effects of 1.3 million transfusions with negative
T&S and short cross match revealed five reports of an acute haemolytic
transfusion reaction (AHTR) (risk of 1:260,000 cross matches). The
responsible antibodies, such as anti-Jka, anti-C, anti-c, anti-Wra and antiKpa could not be demonstrated with the screening, which meant that the
change of AHTR due to antibodies against low frequency antigens is
estimated at 1:650,000 cross matches.
C
Level 3
Shulman 1990
72
Garratty 2003
Schonewille 2003
Level 3
During compatibility studies according to the Type & Screen strategy, the
ABO compatibility between donor and patient is tested and the antibody
screening should be valid and negative.
C
Other considerations
Internationally, the ABO blood group compatibility between donor and patient is checked
during a compatibility study according to the Type & Screen strategy using one of the
following methods:
A short cross match in salt between the erythrocytes of the donor and the
serum/plasma of the patient.
The computer (ABO check of both the recipient and the donor based on recorded
data).
An ABO check of both the recipient and the donor using test reagents (AABB 2008).
The above-mentioned methods have both advantages and disadvantages, which means that
an exact description of the accepted method is essential.
The exclusive checking of the ABO compatibility using a computer (electronic cross match)
without prior control tests of the blood group is insufficient.
Recommendations 3.3.2
1.
2.
o
o
o
3.
o
or
o
For the compatibility study according to the Type & Screen strategy, the antibody
screening should be valid and negative.
If the Type & Screen (T&S) strategy is used, then the following requirements must be
met:
the ABO blood group and the RhD antigen must be known both for the patient and
the donor(s);
screening for irregular erythrocyte antibodies in the patient using a three cell panel of
test erythrocytes;
checking the compatibility of the ABO blood group of the patient and the donor must
be part of the release procedure.
The working group recommends that for the compatibility study according to the Type
& Screen strategy, the ABO blood group compatibility between donor and a recent
sample (max. 72 hours old) of the patient be tested by:
a short cross match in salt between the erythrocytes of the donor and the
serum/plasma of the patient;
the computer. To achieve this, ISBT-128 barcodes on the donor units are used and
an ABO blood group check using test reagents is performed on the patients
erythrocytes. The ABO blood group of the donor unit must have been checked once
before using test reagents in the blood transfusion laboratory of the hospital. This
check should be documented in the computer. The exclusive checking of the ABO
compatibility using a computer (electronic cross match) without prior control tests of
the blood group is insufficient.
73
or
o
ABO blood group checks using test reagents of recipient and donor for each release
of erythrocytes.
Patients who are not eligible for the Type & Screen strategy and for whom a cross match in
the indirect anti-globulin test (IAT) is essential
Scientific support
A number of patient categories, discussed below, are not eligible for the Type & Screen
strategy and the performance of a cross match in the indirect anti-globulin test (IAT) is
essential in these cases (BCSH 2004).
In unborn children and neonates up to the age of three months, passively acquired
antibodies obtained from the mother against a low frequency antigen can be present that
will not be detected by the test erythrocytes. These antibodies are demonstrated in a cross
match in the IAT between the erythrocytes of the donor and preferably the serum/plasma of
the mother. After the first transfusion there is also plasma from the donor present in the
childs circulation. The donor plasma can also contain antibodies against a low frequency
antigen. This means that in subsequent erythrocyte transfusions, the cross match must be
performed using the serum/plasma both from the mother and the child. Antibodies against
low frequency antigens occur primarily in patients who already have IgG antibodies in their
circulation. Therefore, for this group of patients, these antibodies also need to be traced in a
cross match in the IAT between the donors erythrocytes and the serum/plasma of the
patient (BCSH 2004).
A cross match in the indirect anti-globulin test is not strictly necessary for patients with
clinically irrelevant alloantibodies. A cross match can be used to select compatible donor
erythrocytes (see table 3.6.2). In practice, it is usually not possible to find a negative cross
match in IAT for patients with autoantibodies (Lee 2007, Engelfriet 2000).
Patients who have undergone transplantation of a vascularised organ (does not include:
skin, cornea or bone to name a few examples) in the three months prior to blood transfusion
can have anti-A or anti-B antibodies derived from circulating donor lymphocytes in their
circulation, which can only be detected by performing cross matches in the IAT (BCSH
2004).
Such a situation in which anti-A or anti-B antibodies occur can persist for a longer period
and can recur after long periods of time in patients who have undergone an ABO
incompatible bone marrow / stem cell transplant. Therefore, a cross match in the IAT will
always have to be performed for these patients. If a cross match in IAT must be performed,
this test should have at least the same sensitivity as an IAT in bovine albumin (BCSH 2004).
Conclusions 3.3.2
Level 4
74
BCSH 2004
Comment: If clinical circumstances such as prematurity, dysmaturity or a low birth weight hamper
a blood collection from the child in order to perform cross matches, the required cross match with the
serum of the child can be omitted.
Level 4
Level 3
A cross match in the indirect anti-globulin test is not strictly necessary for
patients with clinically irrelevant alloantibodies and autoantibodies. A cross
match can be used to select compatible donor erythrocytes. In practice, it is
usually not possible to find a negative cross match in the indirect antiglobulin test (IAT) for patients with autoantibodies.
C
Level 4
Level 4
BCSH 2004
BCSH 2004
BCSH 2004
Other considerations
Transfusion in the presence of antibodies against low frequency antigens will have a greater
effect on neonates than on adults. In this perspective, a cross match using the
serum/plasma from the mother and if the neonate has already received transfusions also
the serum/plasma from the child is essential (see above-mentioned comment).
Recommendations 3.3.2
Patients who are not eligible for the Type & Screen strategy and for whom a cross match in
the indirect anti-globulin test must be performed are:
1.
recipients of intra-uterine transfusions (both mother and neonate);
75
2.
3.
4.
5.
neonates up to and including the age of three months (perform cross match using at
least serum/plasma from the mother and after transfusion of the neonate also using
serum/plasma from the child), see other considerations;
patients with known, clinically relevant, irregular alloantibodies (see table 3.3);
recipients of transplants of vascularised organs (this does not include skin, cornea or
bone to name some examples) for three months after transplantation.
Patients who have undergone a bone marrow / stem cell transplant.
76
relatively large (in excess of 30%) in patients with autoantibodies(Ahrens 2007, Engelfriet
2000). Therefore, it is important for this group that the presence of alloantibodies be ruled
out (as far as possible), for example using adsorption techniques (Leger 1999, Engelfriet
2000). If this study is not possible due to time constraints, it is preferable to transfuse the
patient with donor erythrocytes that are compatible with the Rhesus phenotype, the K
antigen and the antigens of the Kidd system. Matches for Duffy and Ss antigens are also
preferably indicated (in order of importance), also see other considerations.
In patients with alloantibodies, the chance of additional alloantibody formation is also 20
25%, which is similar to AIHA patients.
As antibodies against erythrocytes can decrease in concentration over time and can then no
longer be demonstrated, it is important to accurately record the data concerning clinically
significant erythrocyte antibodies (Schonewille 2000, Sazama 1990). This registration
concerns the archiving in the laboratory system, the patients medical file and a transfusion
card that is given to the patient. Since May 2007, the start of TRIX (Transfusion Register for
Irregular antibodies and X match problems) in the Netherlands made it possible to store
these data in a national database that can be consulted online by the transfusion
laboratories 24 hours a day (Beunis 2004, TRIX 2009). In the interests of patient safety and
quality considerations, the aim should be to implement rapid national coverage of the
participating laboratories in TRIX. The patient information concerning irregular alloantibodies
and allogeneic stem cell and bone marrow transplants is registered in TRIX. HPA antibodies
and IgA antibodies are also recorded.
Every participating laboratory is authorised to consult TRIX and to register patients in TRIX.
Laboratories that meet the set requirements are authorised to enter irregular antibody data in
TRIX, provided the TRIX criteria have been met (Beunis 2004).
Conclusions 3.3.3
Level 4
Level 4
For patients who are known to have irregular erythrocyte antibodies, one
should be aware for each new transfusion of the occurrence of underlying
antibodies and these antibodies should be ruled out with test erythrocytes
with a maximum validity of 72 hours.
D
Level 3
Level 3
BCSH 2004
77
Other considerations
The antigens of the Rhesus, Kell, Kidd and Ss systems can usually be detected serologically
with monoclonal reagents in patients with warm autoantibodies, provided the person has not
received a transfusion in the past three months. For all other cases (antigens in the Duffy
system and typing of individuals who have received a transfusion in the last three months)
there is the possibility of typing at DNA level (Rozman 2000).
In the case of complex antibody identification, for example due to a combination of several
antibodies, or antibodies targeted against high frequency antigens, the use of various panels
of test erythrocytes is essential. In these types of situations it is desirable to consult a
specialised laboratory.
Recommendations 3.3.3
1.
4.
In order to identify an alloantibody with certainty, the study must meet the following
requirements:
the antibody identification should primarily be performed using the technique with
which the antibodies were demonstrated. Additional techniques can be useful to the
identification, but are not essential.
in order to be able to identify an antibody, the antibody identification must be
performed according to the Fisher exact method (p < 0.05) or the patient
serum/plasma must react with at least two antigen-positive test erythrocytes and at
least two negative cells that do not react per demonstrated antibody;
if there are irregular erythrocyte antibodies present, the erythrocytes of the patient
must also be checked for the absence of the antigen against which the antibodies are
targeted;1
underlying antibodies should be ruled out at least once and preferably two times. This
includes: antibodies against the C, c, D, E, e, K2, Fya, Fyb, Jka, Jkb, M, S and s
antigens must be ruled out using homozygous test erythrocytes, and antibodies
against the K antigen can be ruled out using heterozygous test erythrocytes. If an
anti-RhD antibody is present, the presence of any anti-C and anti-E antibodies may
be ruled out using heterozygous test erythrocytes. In the presence of an anti-c, the
presence of an anti-E may be ruled out using heterozygous test erythrocytes and if
an anti-e is present, the presence of an anti-C antibody may be ruled out in the same
manner.
In patients with clinically relevant autoantibodies, the presence of underlying irregular
erythrocyte antibodies must be ruled out as far as possible before transfusion and
as a preventative measure erythrocytes should be chosen that are compatible with
antigens in the Rhesus system and K. If this exclusion study cannot be performed
(completely), erythrocytes that are compatible for Kidd, Duffy, S and s can also be
considered as a preventative measure.
The validity of the result of the antibody identification study is a maximum of 72 hours
after collection of the sample during the first three months after transfusion or
pregnancy.
The presence of clinically relevant irregular erythrocyte antibodies should be
78
2.
3.
recorded accurately. The working group is of the opinion that this should occur:
in the archives of the blood transfusion laboratory;
in a report from this blood transfusion laboratory to the treating doctor for registration
in the medical file;
*
on a transfusion card that is given to the patient with an explanation that can be
understood by people without a medical background;
*
in TRIX.
5.
In the case of complex antibody identification for example due to a combination of
several antibodies, or antibodies targeted against high frequency antigens the
working group deems the use of various panels of test erythrocytes to be essential. In
these types of situations the working group deems it desirable to consult a
specialised laboratory.
1
: Possibly unreliable result with recent transfusions, unless the units were negative for the
relevant antigen.
2
: see comment 3.3.1
*
*
3.3.4 The use of serum or plasma in antibody screening and cross matches
Scientific support
When screening for the presence of erythrocyte antibodies, clinically relevant antibodies
(IgG and IgM antibodies reactive at 37 C) must be demonstrated, whilst non-specific
positive reactions need to be avoided. Some weak antibodies targeted against antigens in
the Kidd system, for example, can only be demonstrated because they bind complement
(Klein 2005). This means that if less sensitive techniques are used sufficient complement
(in fresh serum) must be present in the test material in order to demonstrate these
antibodies. Complement-binding alloantibodies particularly Kidd are clinically very
important, because they can cause an intravascular haemolytic reaction (Nance 1987).
Hazenberg has demonstrated that the poly-ethylene glycol (PEG)-antiglobulin test and
column method and solid phase method are sensitive enough for demonstrating weak Kidd
antibodies (Hazenberg 1990). The bovine albumin-IAT and the salt-IAT are not sensitive
enough to demonstrate weak Kidd antibodies, if the ability of these antibodies to activate
complement is not used (Klein 2005, Vucelic 2005, AABB 2008). The sensitivity of the
various techniques can be described as follows:
Table 3.3.4:
Technique
Sensitivity
Salt-IAT in tubes
Bovine albumin-IAT in tubes
LISS column test
LISS solid phase
PEG-IAT in tubes
least sensitive
sensitive
most sensitive
most sensitive
most sensitive
Conclusions 3.3.4
Blood Transfusion Guideline, 2011
79
Level 3
Level 3
Level 3
Hazenberg 1990
Recommendations 3.3.4
1.
2.
3.4
The Poly-ethylene glycol (PEG)-anti-globulin tests and LISS column and LISS solid
phase methods are recommended by the working group for demonstrating the
presence of weak Kidd antibodies as these are the most sensitive for demonstrating
weak Kidd antibodies.
Only serum should be used for antibody screening and cross matches with salt-IAT
and bovine albumin-IAT. Serum, heparin-plasma or EDTA-plasma can be used with
the LISS techniques (column and solid phase) and with PEG-IAT.
How to handle data from third parties
General
This chapter proposes that the blood transfusion laboratory is responsible for the release of
compatible blood components. In that framework:
the blood transfusion laboratory may not assume that the label on the blood
component indicates the correct ABO/RhD blood group;
the ABO blood group of the patient must be determined using two, unambiguously
identified blood samples;
known clinically relevant erythrocyte alloantibodies must be taken into consideration.
Other considerations
In order to meet these requirements, every blood transfusion laboratory carefully records
whether the ABO/RhD blood group has been determined (and has been unambiguously
confirmed) for the relevant patient, which blood transfusions this patient has received and
which irregular antibodies if any have been demonstrated in the own laboratory or
elsewhere (i.e. ask for a transfusion card). Prior to each transfusion period, the own hospitalrelated database and the (online) national database TRIX must be consulted. The TRIX
database is particularly important in relation to the increasing patient mobility, which means
that the hospital archive alone cannot meet the set requirements.
80
In practice, we can distinguish between four situations in which data from third parties is
important:
The ABO/RhD blood group of the patient has been determined at another institution.
The patient is registered at another institution as having irregular erythrocyte
alloantibodies.
Transfusion of neonates who were transfused at another institution (intra-uterine).
Allogeneic stem cell and bone marrow transplantation, which can change the
ABO/RhD blood group of the patient.
Recommendations 3.4
1.
2.
3.
4.
3.5
The working group is of the opinion that for the release of compatible blood
components every blood transfusion laboratory should carefully record whether the
ABO/RhD blood group has been determined (and has been unambiguously
confirmed) for the relevant patient, which blood transfusions this patient has received
and which irregular antibodies if any have been demonstrated in the own
laboratory or elsewhere (i.e. ask for a transfusion card). This hospital-related
database and the (online) national database TRIX should be consulted for verification
prior to each transfusion.
In emergency situations, an ABO/RhD blood group determined by a third party may
be considered as a one-off independently determined blood group if the blood
transfusion laboratory has access to (a copy of) an official (i.e. visibly authorised)
report with the correct identification data and the definitive blood group.
There must be a procedure in place in the hospital to record the result of irregular
erythrocyte antibodies determined by third parties as such with source reporting.
For an intra-uterine transfusion and/or (exchange) transfusion in a neonate, the blood
transfusion laboratory should check if necessary whether the mothers (recent)
transfusion history is known.
Release and transfer of blood components
81
Level 3
Level 3
Six to twenty percent of the errors were made during the selection of blood
components from the stock and during the transfer of these components
from the blood transfusion laboratory to the ward.
C
Other considerations
When blood components that have been declared compatible are released to the ward,
there is a transfer of the responsibility from the blood transfusion laboratory to the ward. The
procedure up to and including the administration of blood components should be recorded
and registered within legal parameters using a sound administrative system. Checks are
performed to prevent administrative mix-ups.
Examples of such a checking procedure for the release of blood components from the blood
transfusion laboratory to the ward are described in table 3.5 below.
Table 3.5: Example of a checking procedure for release of blood components from the blood
transfusion laboratory to the ward in order to prevent administrative mix-ups
Advice
Objective
requested component
Tracing of errors in
identification of patient
Traceability of the
transfer of the
responsibility
In order to prevent errors, it is preferable that one unit of blood component is released per
patient, per time by the blood transfusion laboratory to a ward, instead of several units
simultaneously. Exceptions are made for wards that have a validated and monitored blood
storage refrigerator. Each blood component is then accompanied by a form. For the
administration, it is also important that there is a sound registration process preferably
using an electronic transfusion monitoring system that shows which blood component has
actually been administered to which patient at which time. In accordance with European
legislation, this registration is stored for a minimum of 30 years.
82
Recommendations 3.5.1
1.
2.
3.
4.
5.
3.6
The procedure for the transfer of blood components from the blood transfusion
laboratory to the ward should be recorded in writing.
This procedure should describe checks that are performed to prevent possible
administrative mix-ups. An example of a checking procedure is described in table
3.5.
If possible, the blood transfusion laboratory releases one unit of blood component
per patient, per time to a ward. Exceptions are made for wards that have a validated
and monitored blood storage refrigerator.
The blood transfusion laboratory must supply an (electronic) accompanying form to
the ward with each blood component.
A sound registration procedure preferably using an electronic transfusion
monitoring system should take place that shows which blood component was
actually administered to which patient at which time. In accordance with European
legislation, this administration should be stored for 30 years.
Selection of erythrocyte concentrate
83
2nd
3rd
4th
O pos
O pos
O neg
O neg
O neg
A pos
A pos
A neg
O pos
O neg
A neg
A neg
O neg
B pos
B pos
B neg
O pos
O neg
B neg
B neg
O neg
AB pos
AB pos
AB neg A pos
A neg
AB neg
AB neg A neg
B neg
5th
6th
B pos
B neg
7th
8th
O pos
O neg
O neg
The following paragraphs discuss specific patient groups, for whom additional requirements
apply to the selection of ABO/RhD compatible units of erythrocyte concentrate.
Conclusions 3.6.1
Level 4
An extra burden is placed on the donor population with blood group O RhD
negative. A shortage of erythrocyte concentrates of this blood group can
occur.
D
Level 4
Other considerations
1.
The risk of anti-RhD formation in patients who have received RhD incompatible
transfusions is 20 30% (Frohn 2003, Yazer 2007, Gonzales-Porrez 2008)
2.
The chance of the presence of anti-RhD antibodies is smaller in male RhD negative
patients than in female RhD negative patients, who can become immunised through
pregnancy.
3.
The clinical importance of the development of anti-RhD antibodies is less important in
RhD negative men than in RhD negative women < 45 years of age. In RhD negative
women of childbearing age, the presence of anti-D antibodies can cause
complications for the foetus during pregnancy and can also have consequences for
the neonate. For the selection of RhD identical units, it is recommended that negative
units be selected for women younger than 45 years if the RhD blood group has not
been determined with certainty. For men with a negative antibody screening, the
selection of RhD identical units can be considered for a one-off RhD determination.
In emergencies, women over the age of 45 years and men with unknown RhD blood
group can also receive RhD positive units (Gonzalez 2008).
84
Recommendations 3.6.1
1.
2.
3.
Patients should preferably receive transfusions with ABO and RhD identical
erythrocytes.
It is essential that the hospitals take the necessary logistical measures to reduce the
unnecessary use of blood group O RhD negative erythrocytes.
For the selection of RhD identical units, it is recommended that negative units be
selected for women younger than 45 years if the RhD blood group has not been
determined with certainty. For men with a negative antibody screening, the selection
of RhD identical units can be considered after a one-off RhD determination. In
emergencies, women over the age of 45 years and men with unknown RhD blood
group can also receive RhD positive units.
85
clinically relevant
antigen negative
anti
A, B, AB
C
c
D
E
e
Cw
other rhesus
A1
M
M
N
S
s
U
other MNSs
P1
Lu
b
Lu
other lutheran
Le
b
Le
K
k
other Kell
Fy
b
Fy
other Duffy
Jk
b
Jk
other Kidd
Wra
Yt
Yt
Colton b
LW
Chido/Rodgers
H
H, IH,
Knops en Cost
P, Tja
Vel
LFA (other)*
HFA (other)**
yes
yes
yes
yes
yes
yes
37 C reactive
yes
37 C reactive
37 C reactive
not reactive 37 C
37 C reactive
yes
yes
yes
yes
37 C reactive
37 C reactive
yes
yes
37 C reactive
37 C reactive
yes
yes
yes
yes
yes
yes
yes
yes
yes
37 C reactive
yes (strong)
no (weak)
37 C reactive
yes
no (weak)
yes (allo)
37 C reactive (auto)
no
yes
yes
consult reference lab
consult reference lab
yes
yes
yes
yes
yes
yes
no
yes
no
yes
no
no
yes
yes
yes
consult ref. lab
no
no
yes
yes
no
no
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes, optional
yes
no
no
no
no
yes
no
no
yes
yes
N/A
N/A
X match IAT
X match IAT
compulsory
selection
N/A
yes
yes
yes
yes
yes
N/A
yes
N/A
yes
N/A
N/A
yes
yes
yes
N/A
N/A
N/A
yes
yes
N/A
N/A
yes
yes
yes
yes
yes
yes
yes
yes
yes
N/A
yes
N/A
N/A
N/A
N/A
N/A
N/A
N/A
yes
yes
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
yes
N/A
yes
N/A
yes
yes
N/A
N/A
N/A
N/A
yes
yes
N/A
N/A
yes
yes
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
yes
N/A
yes
yes
yes with D neg
yes
N/A
N/A
yes
N/A
N/A
N/A
N/A
86
Conclusion 3.6.2
The clinically relevant allo (erythrocyte) antibodies included in table 3.6.2
are antibodies that can cause haemolytic transfusion reactions.
Level 3
C
Daniels 2002
Patients who have previously formed a clinically relevant antibody will as a general rule
form a second antibody against a foreign antigen more quickly. In a Dutch patient population
of nearly 1000 patients with various conditions, the chance of additional antibody formation
was 20 25% (Schonewille 2006, 2009).
Recommendations 3.6.2
1.
2.
3.
4.
5.
3.7
For patients known to have clinically relevant allo-erythrocyte antibodies, only blood
from which the relevant antigen is missing should be selected. In addition to the use
of typed erythrocytes, a cross match in the IAT should also be performed.
For patients with clinically irrelevant alloantibodies against erythrocytes, a negative
cross match performed in the indirect agglutination test is sufficient if this result is
negative.
For patients with known erythrocyte antibodies, the treating doctor must weigh the
risk of transfusion reactions due to non-selected units against the risk of delaying the
blood transfusion until compatible units have been found.
Patients who have previously formed a clinically relevant antibody will as a general
rule form a second antibody against a foreign antigen more quickly. In order to rule
out antibodies against specific (private) antigens, a complete cross match (including
indirect anti-globulin phase) should always be performed during the compatibility
study.
It is recommended that rhesus phenotype and K compatible erythrocytes be
administered to recipients with clinically relevant alloantibodies, in order to prevent
further antibody formation.
Selection of erythrocytes for specific patient categories
In addition to the patients with clinically relevant alloantibodies discussed above for whom
compatible units must be selected with the aid of table 3.6.2 there are other specific patient
categories, for whom additional requirements are set:
1.
Girls and women younger than 45 years
2.
Patients with haemoglobinopathies, such as sickle cell anaemia or thalassaemia
3.
Patients with an auto-immune haemolytic anaemia
4.
Patients with a myelodysplastic syndrome (MDS)
5.
Patients exposed to hypothermia
87
The use of cEK-compatible blood for girls and women younger than 45 years of age relates
to the prevention of antibody formation and thereby prevention of haemolytic disease of the
newborn. In addition to RhD antibodies, other irregular antibodies can also be responsible
for this. The most commonly occurring non-D antibodies in Caucasian patients responsible
for the haemolytic disease of the newborn are anti-K and anti-c and to a lesser extent antiE (Koelewijn 2009, Castel 1996, van Dijk 1991, Contreras 1991).
In the Caucasian population, 91% is negative for the K-antigen and 9% is positive.
The large majority of the Dutch donor population is typed for the rhesus phenotype (C, c, D,
E and e) and the K-type (K negative or K positive). (communication Sanquin BloodSupply ).
A Health Council Committee on Pregnancy Immunisation concluded in its report in 2009 that
it is recommended to give erythrocytes that are compatible with regard to the antigens c, E
and K during blood transfusion to girls and women up to the age of 45 years (Health Council
2009). It was left up to the professionals to determine how this recommendation is
implemented.
Conclusions 3.7.1
Level 3
Level 4
Koelewijn 2009
Castel 1996, Van Dijk 1991, Contreras 1991
Recommendation 3.7.1
In order to reduce the number of cases of haemolytic disease of the newborn due to anti-K,
anti-c and anti-E as much as possible, all women aged 45 years and younger should be
transfused with K, c and E compatible units. It is not necessary to type these women for the
K antigen first. If the typing of the K antigen for the patient is known, then K compatible blood
can also be transfused.
3.7.2 Selection of erythrocytes for patients with haemoglobinopathies (see also
Chapter 4)
Scientific support
In patients with haemoglobinopathies (sickle cell anaemia or thalassaemia) who regularly
require transfusions, there is a high degree of allo-immunisation when unselected blood is
administered. The study by Ness et al has shown this to 10% in children and up to 50% in
adults with sickle cell anaemia (Ness 1994). Olujohungbe et al state a figure of 76% allo-
88
immunisation in patients with sickle cell anaemia in the United Kingdom (Olujohungbe 2001),
primarily caused by racial differences between donor and recipient (Vishinski 1990).
What probably played a role in these studies is the fact that a group of primarily Negroid
patients was transfused with blood from white donors, who have different frequencies of
blood groups. This was also the case in the Netherlands. Spanos described a similar
phenomenon in patients with thalassaemia (Spanos 1990). Therefore, transfusiondependent patients with haemoglobinopathies should be typed as early as possible for the
blood groups of the Rhesus, Kell, Duffy, Kidd and MNS systems, and the very rare S and s
negative patients should also be typed for blood group U (BCSH 2008).
There are no control studies that examine the effect of matching to prevent alloantibody
formation. Three observational studies support the matching for the complete rhesus
phenotype and blood group K (Wayne 1995, Pearlman 1994, Russel 1984).
In the case where patients have already been transfused, typing of the Rhesus, Kell, Duffy,
Kidd and Ss antigens is possible at DNA level (BCSH 2004, Armeen 2003; Ribeiro 2009,
Castilho 2002, 2002, Rozman 2000).
The degree of immunisation in these patients decreases as a result of selection of rhesus
phenotype compatible and K negative blood. (BCSH 2004, Armeen 2003). A recent study
has also shown that the blood groups Fy a, Jkb, S and s are also important (in order of
importance). By selecting Fya, Jkb, S en s negative erythrocytes respectively for patients who
are negative for these antigens (in order of importance), the degree of immunisation can be
decreased significantly (Schonewille 2006). As the frequency of Jkb neg (51%) is greater
than Jka neg (8%) in patients with sickle cell anaemia, particularly Jk b compatible
transfusions are important for these patients in order to prevent immunisation.
Extensive selection of blood negative for these antigens can result in far-reaching reduction
of allo-immunisation (Schonewille 2006, Castro 2002, Tahhan 1994).
Conclusions 3.7.2
Level 4
Level 2
Three observational studies support the matching for the complete rhesus
phenotype and blood group K.
B
Level 2
BCSH 2008
If the patient has already been transfused, typing of Rhesus, Kell, Duffy,
Kidd and Ss antigens at DNA level is possible. The degree of immunisation
in these patients decreases as a result of selection of rhesus phenotype
compatible and K negative blood.
B
89
Level 3
Level 3
Schonewille 2006
For patients with sickle cell anaemia, the frequency of Jk b neg (51%) is
greater than Jka neg (8%). Therefore, Jkb compatible transfusion is
important for these patients in order to prevent immunisation. More
extensive selection of blood negative for these antigens can result in farreaching reduction of allo-immunisation.
C
Other considerations
The selection choice of the compatible units is partly determined by the antigen
determinations performed and the availability of typed units in the blood bank.
Recommendations 3.7.2
1.
2.
Level 3
Engelfriet 2000
Other considerations
90
As the chance of alloantibody formation is relatively large in patients with AIHA due to
clinically relevant autoantibodies, it is important for this group to prevent (as far as possible)
the formation of alloantibodies by transfusion with erythrocytes that are Rhesus phenotype
and K compatible. Preferably, matches for Kidd, Duffy and Ss antigens are also indicated (in
order of importance), if the presence of alloantibodies cannot be ruled out. The antigens of
the Rhesus, Kell, Kidd and Ss systems can usually be detected serologically with
monoclonal reagents if the patient has not received a transfusion in the past three months.
For all other cases (antigens in the Duffy system and typing of individuals who have received
a transfusion in the last three months) there is the possibility of typing at DNA level (Rozman
2000).
Recommendation 3.7.3
If possible, rhesus phenotype and K compatible blood should be selected for patients with
AIHA in order to prevent alloantibody formation.
3.7.4 Selection of erythrocytes for patients with myelodysplastic syndrome
The available literature is ambiguous, but according to an analysis based on this literature,
the risk of immunisation in patients with myelodysplastic syndrome (MDS) varies between 14
and 59% - average of 23% - and is comparable to SCD and thalassaemia (Schonewille
2008). It is therefore recommended to select rhesus phenotype and K compatible blood for
these patients (Fluit 1990, Novaretti 2001, Stiegler 2001, Schonewille 1999, Arriaga 1995).
Conclusion 3.7.4
The immunisation risk for patients with MDS varies between 14 and 59%.
Level 3
Fluit
1990,
Arriaga1995,
Novaretti
2001,
Stiegler
2001;
Schonewille 1999
Other considerations
In two Dutch studies of patients with myeloproliferative neoplasmata (MPN), in which 44
(Schonewille 1999) and 16 (Fluit 1990) patients respectively were included, the
immunisation risk was on average 17%. No new studies with larger patient groups have
been published.
Recommendation 3.7.4
Taking into consideration the immunisation risk in patients with MDS, it is preferable to
transfuse these patients with rhesus phenotype and K compatible blood.
3.7.5 Selection of erythrocytes for surgical procedures with hypothermia in patients
with cold antibodies
Clinically relevant cold antibodies in patients undergoing interventions with hypothermia such
as cardiac surgery can cause transfusion reactions (Hoffman 2002). The transfusion
reactions described in older publications only occurred with strong cold antibodies and/or
deep (~15 C) hypothermia. Strong cold antibodies can cause problems in the standard
91
compatibility tests and deep hypothermia is now only used in combination with specific
interventions.
There is no evidence in the literature to support pre-operative screening for cold antibodies
at room temperature for all patients being exposed to mild hypothermia (~ 30 C). (Judd
2006).
Conclusions 3.7.5
Level 4
Level 4
Hoffman 2002
Judd 2006
Other considerations
The transfusion reactions described in the literature only occurred in the case of the
presence of strong cold antibodies and/or in surgery involving deep hypothermia. Following
consultation with the anaesthesiologist, it may be desirable in some cases to determine the
frequency of the clinically relevant cold antibody.
Recommendation 3.7.5
It is not necessary to perform pre-operative screening for cold antibodies at room
temperature on patients undergoing a surgical procedure with mild hypothermia (~ 30 C).
3.8
is not always possible in HLA-typed transfusions and therefore the anti-A and/or anti-B titre
should be monitored regularly (particularly in the case of poor yield).
Level 3
Both the quantity and the biological activity of anti-A and/or anti-B
antibodies in the recipient and the density of the ABO antigens on the
membrane of the donor platelets determine the final yield of the platelets.
B
Ogasawara 1993
Level 1
Other considerations
If the expected increase in platelet number is not achieved in a stable patient, the CI (count
increment) or CCI (corrected count increment) should be determined after transfusion with
(fresh) ABO compatible platelets.
In the case of an ABO incompatible platelet transfusion, it is important to be aware of
individual variations in the extent to which ABO incompatible platelets are degraded
(variation in anti-A and anti-B respectively in the recipient and antigen density in the donor).
93
nd
rd
B or A
B*
A*
AB
(AB)
th
Option * only after consultation with the head of the transfusion department (double incompatibility)
Comment: Platelet hyper-concentrates are also available for blood group incompatibilities (see also
paragraph 2.1.4).
Recommendations 3.8.1.1
1.
2.
Conclusions 3.8.1.2
Level 3
Level 3
Mair 1998
Larsson 2000, Lozano 2003, Harris 2007
Valbonesi 2000
Recommendations 3.8.1.2
1.
2.
3.
95
Platelet transfusions should preferably be RhD compatible. RhD negative female patients <
45 years old should receive only RhD negative platelet concentrates; if transfusion of RhD
positive platelet concentrate is unavoidable, possible immunisation should be avoided by the
administration of an ampoule of anti-RhD immunoglobulin containing 375 international units
(IU) (Lozano 2007).
Conclusion 3.8.2.2
Level 3
There are indications that the minimum quantity of erythrocytes that can
cause primary RhD immunisation is 0.03 mL.
C
Level 3
Goldfinger 1971
Lozano 2003, Atoyebi 2000
Recommendation 3.8.2.2
It is recommended that platelet transfusions should preferably be RhD compatible. Female
RhD negative patients under the age of 45 years should only receive RhD negative platelet
concentrates. If this cannot be achieved, an ampoule of anti-RhD immuno-globulin
containing 375 international units (IU) should be administered (provides roughly 10 weeks of
protection) to prevent RhD immunisation.
3.9
Release of plasma
Plasma is released as blood group ABO compatible, as plasma can contain antibodies
against blood group antigens A and B. A recent cohort study showed that transfusion of ABO
incompatible plasma after organ transplantation was associated with more multi-organ
damage and that in a surgical population administration of ABO compatible but not ABO
identical plasma was associated with a higher mortality than administration of ABO identical
plasma (Benjamin 1999, Shanwell 2009). This could be caused by soluble immune
complexes of soluble A and/or B + anti-A and/or anti-B antibodies (Shanwell 2009).
The ABO blood group of the recipient should be determined and confirmed using at least two
independently collected samples (see paragraph 3.2.1 and 3.2.2). If the ABO blood group is
unknown or has only been determined once, AB plasma should be administered. As the
apheresis plasma in the Netherlands is prepared using a method in which the the remaining
erythrocyte number is less than 1 x 10 8/unit, the RhD blood group does not have to be taken
into consideration. All donors are tested for irregular antibodies and are negative or have a
titre lower than 32. (Vrielink 2004).
Conclusion 3.9
96
Benjamin 1999
Shanwell 2009
Other considerations
European legislation means that it is compulsory for the RhD blood group to be stated on the
label of the plasma component.
Table 3.9: Selection of ABO compatible plasma
Recipient
nd
AB
AB
AB
AB
rd
th
AB
The working group deems it important that a visual inspection for colour (due to
contamination with erythrocytes), clots and leakage of the bag takes place before release of
a unit of plasma.
Recommendations 3.9
1.
2.
3.
Plasma should be administered ABO blood group compatible (see table 3.9 Selection
of ABO compatible plasma).
Further investigation to determine whether plasma transfusions need to be ABO
identical is recommended. For plasma transfusion, it is not necessary to take into
consideration the RhD blood group.
The unit of plasma is checked for colour, clots and leakage before release.
Literature 3.1
1.
2.
3.
4.
5.
6.
7.
Dzik, W.H., Murphy, M.F., Andreu, G., Heddle, N., Hogman, C., Kekomaki, R., Murhy, S.,
Shimizu, M. & Smit-Singa, C. (2003) An international study of the performance of blood
sample collection. Vox Sanguinis, 85, 4047.
Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State.
Transfusion 1992;32:601-6.
Linden JV, Wagner K, Voytovich AE, Sheehan J. Transfusion errors in New York State: an
analysis of 10 years experience. Transfusion 2000;40:1207-13.
Love EM, Jones H, Williamson LM, Cohen H, et al. Serious hazards of transfusion (SHOT):
summary of annual report 1999-2000. March 2001.
Murphy, M.F., Stearn, B.E. & Dzik, W.H. (2004) Current performance of patient sample
collection in the UK. Transfusion Medicine, 14, 113121.
Stainsby D, Russell J, Cohen H, Lilleyman J. BJH 2005; 131. 8-12.
TRIP-rapporten 2003 t/m 2007.
97
8.
Williamson LM, Lowe S, Love E, Cohen H, Soldan K, McCleland DBL, et al. Serious hazards
of transfusion (SHOT) initiative: analysis of the first two annual reports. BMJ 1999;319:16-9.
Literature 3.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
Andreu, G., Morel, P., Forestier, F., Debier, J., Rebibo, D., Janvier, G. & Herve, P. (2002)
Haemovigilance network in France: organisation and analysis of immediate transfusion
incident reports from 1994 to 1998. Transfusion, 42, 13561364.
Guide to the preparation, use and quality assurance of blood components , 14e editie, 2008,
Council of Europe, pag 227 ISBN 978-92-871-6330-1.
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State.
Transfusion. 1992 Sep;32(7):601-6.
Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion.
1990 Sep;30(7):583-90.
Stainsby D, Russell J, Cohen H, Lilleyman J. BJH 2005; 131. 8-12.
TRIP-rapporten 2003 t/m 2007.
Williamson LM, Lowe S, Love E, Cohen H, Soldan K, McCleland DBL, et al. Serious hazards
of transfusion (SHOT) initiative: analysis of the first two annual reports. BMJ 1999;319:16-9.
Literature 3.2.1
1.
2.
3.
4.
Literature 3.2.2
1.
2.
98
3.
4.
5.
6.
7.
8.
Gonzales-Porras JR, Graciani IF, Perez-Simon JA, Martin-Sanchez J, Encinas C, Conde MP,
Nieto MJ, Corral M. Prospective evaluation of a transfusion policy of D+ red blood cells into
D- patients. Transfusion 2008; 48:1318-1324.
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Klein HG, Anstee DJ Mollisons Blood Transfusion in Clinical Medicine 11th edition, 2005,
Blackwell publishing.
Mollison PL, Engelfriet CP, Contreras M. Blood Transfusion in clinical Medicine. 10th edition.
Oxford: Blackwell Science Ltd., 1997. p. 169-70.
Mollison PL, Engelfriet CP, Contreras M. Blood Transfusion in clinical Medicine. 10th edition.
Oxford: Blackwell Science Ltd., 1997. p.343-48.
Jones ML, Wray J, Wight J, Chilcott J, Forman K, Tappenden P, et al. A review of the clinical
effectiveness of routine antenatal anti-D prophylaxis for rhesus-negative women who are
pregnant. BJOG 2004 Sep;111(9):892-902
Literature 3.2.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Brown PL. Resolving ABO typing discrepancies and other typing problems. In: Rudmann SV
(ed). Textbook of blood banking and transfusion medicine. 2nd edition. Philadelphia:
Saunders Company, 2005, Section 4 part 13.
Dzik, W.H., Murphy, M.F., Andreu, G., Heddle, N., Hogman, C., Kekomaki, R., Murhy, S.,
Shimizu, M. & Smit-Singa, C. (2003) An international study of the performance of blood
sample collection. Vox Sanguinis, 85, 4047
Ibojie J, Urbaniak SJ. Comparing near misses with actual mistransfusion events: a more
accurate reflection of transfusion errors. Br J Haematol 2000;108:458-60.
Inspectierapport Sanguis sanus sanat. Uitgave Inspectie voor de Gezondheidszorg 2001;32.
Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State.
Transfusion 1992;32:601-6.
Linden JV, Wagner K, Voytovich AE, Sheehan J. Transfusion errors in New York State: an
analysis of 10 years experience. Transfusion 2000;40:1207-13.
Sazama K. Reports of 355 transfusion-associated deaths: 1976-1985. Transfusion
1990;30:583-90.
Shulman IA, Downes KA, Sazama K, Maffei LM. Pretransfusion compatibility testing for red
blood cell administration. Curr Opin Hematol 2001;8:397-404.
99
12.
13.
14.
15.
Literature 3.3.1
1.
2.
3.
4.
Literature 3.3.1
1.
2.
3.
4.
Redman M, Regan F, Contreras-M. A prospective study of the incidence of red cell alloimmunisation following transfusion. Vox Sang 1996;71:216-20.
Schonewille e.a. Additonal red blood cell alloantibodies after blood transfusions in a
nonhematologic alloimmunized patient cohort: is it time to take precautionary measures?
Transfusion 2006;46:630-635.
Schonewille e.a. Red blood cell alloantibodies after transfusions: factors influencing
incidence and specificity, Transfusion 2006;46:250-256.
Shulman IA, Nelson JM, Nakayama R. When should antibody screening tests be done for
recently transfused patients. Transfusion 1990;30:39-41.
Literature 3.3.2
1.
2.
3.
100
4.
5.
6.
7.
8.
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Schonewille H, van Zijl AM, Wijermans PW. The importance of antibodies against lowincidence RBC antigens in complete and abbreviated cross-matching. Transfusion
2003;43:939-44.4.
Shulman IA, Nelson JM, Saxena S, Thompson JC, Okamoto M, Kent DR, et al. Experience
with the routine use of an abbreviated crossmatch. Am J Clin Pathol 1984;82:17881.Standards for Blood Banks and transfusion services, 26e editie, AABB.
Shulman IA. The risk of an overt hemolytic transfusion reaction following the use of an
immediate spin crossmatch. Arch Pathol Lab Med. 1990 Apr;114(4):412-4.
Williamson LM, Lowe S, Love EM, Cohen H, Soldan K, McClelland DB, et al. Serious hazards
of transfusion (SHOT) initiative: analysis of the first two annual reports. BMJ 1999 Jul
3;319(7201):16-9.
Literature 3.3.2
1.
2.
3.
Engelfriet.C.P. et al The detection of alloantibodies against Red cells in Patients with warmtype autoimmune haemolytic anaemia. Vox Sanguinis 2000;78:200-207.
Guidelines for compatibility procedures in blood transfusion laboratories, BCSH, Transfusion
Medicine, Volume 14, Issue 1, Date: February 2004, Pages: 59-73.
Lee.E et al Do patients with autoantibodies or clinically insignificant alloantibodies require
anindirect antiglobulintest crossmatch? transfusion 2007 47 (7).
Literature 3.3.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
Engelfriet C.P. et al The detection of alloantibodies against red cells in warm type Auto
immune haemolytic anaemia. Vox sanguinis 2000 78 (3) 200-207.
Fluit CR, Kunst VA, Drenthe-Schonk AM. Incidence of red cell antibodies after multiple blood
transfusions. Transfusion 1990;30:532-5.
Guidelines for compatibility procedures in blood transfusion laboratories, BCSH, Transfusion
Medicine, Volume 14, Issue 1, Date: February 2004, Pages: 59-73.
M.H. Beunis, R.J.T. Smeenk: Transfusie Register Irregulaire Antistoffen en X-proef
problemen: Van RITA met CLAUS naar TRIX. Nederlands Tijdschrift voor Bloedtransfusie;
dec 2004: 13-21.
Rozman P, Dovc T, Gassner C. Differentiation of autologous ABO, RHD, RHCE, KEL, JK,
and FY blood group genotypes by analysis of peripheral blood samples of patients who have
recently received multiple transfusions. Transfusion 2000 Aug;40(8):936-42.
Sazama K. Reports of 355 transfusion associated deaths 1976-1985. Transfusion
1990;30:583-90.
Schonewille H, Haak HL, Zijl AM van. RBC antibody persistence. Transfusion 2000;40:112731.
Schonewille H, van de Watering LM, Loomans DS, Brand A. Red blood cell alloantibodies
after transfusion: factors influencing incidence and specificity. Transfusion. 2006;46:250-6.
TRIX procedures: www.sanquin.nl/diagnostiek/TRIX. 2009.
101
10.
11.
Leger RM, Garratty G. Evaluation of methods for detecting alloantibodies underlying warm
autoantibodies. Transfusion 1999 Jan;39(1):11-6.
Ahrens N, Pruss A, Kahne A, Kiesewetter H, Salama A. Coexistence of autoantibodies and
alloantibodies to red blood cells due to blood transfusion. Transfusion 2007 May;47(5):813-6.
Literature 3.3.4
1.
2.
3.
4.
5.
6.
7.
Bromilow IM, Eggington JA, Owen GA, Duguid JK. Red cell antibody screening and
identification: a comparison of two column technology methods. Br J Biomed Sci
1993;50:329-33.
Guidelines for compatibility procedures in blood transfusion laboratories, BCSH, Transfusion
Medicine, Volume 14, Issue 1, Date: February 2004, Pages: 59-73.
Hazenberg CAM, Mulder M, Beele JM. Erythrocyte antibody screening in solid phase: A
comparion of two solid phase microplate assays with the Indirect Antiglobulin Test in
Polyethylene Glycol for the detection of irregular Erytrocyte Antibody. Vox Sang 1990;59:96100.
Man AJ de, Overbeeke MA. Evaluation of the polyethylene glycol antiglobulin test for
detection of red blood cell antibodies. Vox Sang 1990;58:207-10.
Nance SJ, Garratty G. A new Potentiator of Red Blood Cell Antigen-Antibody Reactions. Am J
Clin Pathol 1987;87:633-5.
Standards for Blood Banks and transfusion services, 26e editie, AABB.
Vucelic D, Savic N, Djordjevic R. Delayed hemolytic transfusion reaction due to anti-Jk(a).
Acta Chir Iugosl 2005;52(3):111-5.
Literature 3.5.1
1.
2.
3.
4.
5.
6.
Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State.
Transfusion 1992;32:601-6.
McClelland DBL, Phillips P. Errors in bloodtransfusion in Britain: Survey of hospital
haematology departments. BMJ 1994;308:1205-6.
Sazama K. Reports of 355 transfusion associated deaths 1976-1985. Transfusion
1990;30:583-90.
Stainsby D, Jones H, Asher D, Atterbury C, Boncinelli A, Brant L, et al. Serious hazards of
transfusion: a decade of hemovigilance in the UK. Transfus Med Rev 2006;20:273-82.
Stainsby D. ABO incompatible transfusions--experience from the UK Serious Hazards of
Transfusion (SHOT) scheme Transfusions ABO incompatible. Transfus Clin Biol
2005;12:385-8.
Williamson LM, Lowe S, Love EM, Cohen H, Soldau K, McClelland DBL, et al. Serious
Hazards of Bloodtransfusion (SHOT) initiative analyses of the first two annual reports. BMJ
1999;319:16-9.
Literature 3.6.1
102
1.
2.
3.
4.
Gonzales-Porraz JR, Graciani IF, Perez-Simon JA, Martin-Sanchez J, Encinas C, Conde MP,
Nieto MJ, Corral M. Prospecitve evaluation of a transfusion policy of D+ red blood cells into
D- patients. Transfusion 2008;48:1318-1324.
Jaarverslag Sanquin 2008.
Frohn C, Dumbgen L, Brand JM, Gorg S, Luhm J, Kirchner H. Probability of anti-D
development in D- patients receiving D+ RBCs. Transfusion 2003 Jul;43(7):893-8.
Yazer MH, Triulzi DJ. Detection of anti-D in D- recipients transfused with D+ red blood cells.
Transfusion 2007 Dec;47(12):2197-201.
Literature 3.6.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
Fluit CR, Kunst VA, Drenthe-Schonk AM. Incidence of red cell antibodies after multiple blood
transfusion. Transfusion 1990;30:532-5.
G.Daniels. Human Bloodgroups, Blackwell Science, 2002
Guidelines for compatibility procedures in blood transfusion laboratories, BCSH, Transfusion
Medicine, Volume 14, Issue 1, Date: February 2004, Pages: 59-73
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Klein HG, Anstee DJ Mollisons Blood Transfusion in Clinical Medicine 11th edition, 2005,
Blackwell publishing.
Mollison PL, Engelfriet CP, Contreras M. Blood Transfusion in clinical Medicine. 10th edition.
Oxford: Blackwell Science Ltd., 1997;325-6:365.
Schonewille H, Brand A. Alloimmunization to red blood cell antigens after universal
leucodepletion. A regional multicentre retrospective study. Br J Haematol 2005
Apr;129(1):151-6.
Schonewille H, van de Watering LM, Brand A. Additional red blood cell alloantibodies after
blood transfusions in a nonhematologic alloimmunized patient cohort: is it time to take
precautionary measures? Transfusion 2006 Apr;46(4):630-5.
Schonewille H, de Vries RR, Brand A. Alloimmune response after additional red blood cell
antigen challenge in immunized hematooncology patients. Transfusion 2009 Mar;49(3):453-7.
Literature 3.7.1
1.
2.
3.
4.
5.
Castel A, Dijk BA van, Boom FMLG van, Brand A, Engelfriet CP, Overbeeke MAM, et al.
Preventie van immunisatie door c, E en K: achtergronden en gefaseerde implementatie. Ned
Tijdschr Klin Chemie 1996;21:3-7.
Contreras M, Knight RC. Controversies in transfusion medicine. Testing for Du: con.
Transfusion 1991;31:270-2.
Detection and prevention of pregnancy immunisation. The OPZI study. Academic thesis J.M.
Koelewijn. Amsterdam 2009.
Dijk B van. Irregulair bloedgroepantagonisme: een geregeld probleem [proefschrift].
Rijksuniversiteit Leiden 1991. p. 119-49.
Gezondheidsraad:
Zwangerschapsimmunisatie
door
rode
cellen,
Den
Haag:
Gezondheidsraad, 2009, publicatienummer 2009/04.
103
Literature 3.7.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Literature 3.7.3
104
1. Engelfriet et al the detection of alloantibodies against red cells in warm type AIHA. Vox
sanguinis 2000 78 (3) 200-207.
2. Rozman P, Dovc T, Gassner C. Differentiation of autologous ABO, RHD, RHCE, KEL, JK,
and FY blood group genotypes by analysis of peripheral blood samples of patients who have
recently received multiple transfusions. Transfusion 2000 Aug;40(8):936-42.
Literature 3.7.4
1. Arriaga F, Bonanad S, Larrea L, de la RJ, Lopez F, Sanz MA, et al. Immunohematologic
study in 112 patients with myelodysplastic syndromes: 10-year analysis. Sangre (Barc
)1995;40:177-80.
2. Novaretti MC, Sopelete CR, Velloso ER, Rosa MF, Dorlhiac-Llacer PE, Chamone DA.
Immunohematological findings in myelodysplastic syndrome. Acta Haematol 2001;105:1-6
3. Schonewille H, Haak HL, van Zijl AM. Alloimmunization after blood transfusion in patients with
hematologic and oncologic diseases. Transfusion 1999;39:763-71.
4. Stiegler G, Sperr W, Lorber C, Fabrizii V, Hocker P, Panzer S. Red cell antibodies in
frequently transfused patients with myelodysplastic syndrome. Ann Hematol 2001;80:330-3
5. Fluit CR, Kunst VA, Drenthe-Schonk AM. Incidence of red cell antibodies after multiple blood
transfusions. Transfusion 1990;30:532-5
6. Schonewille H. Red blood cell alloimmunization after blood transfusion. Thesis, Leiden
University, 2008
Literature 3.7.5
1.
2.
Hoffman JW Jr, Gilbert TB, Hyder M. Cold agglutinins complicating repair of aortic dissection
using cardiopulmonary bypass and hypothermic circulatory arrest: case report and review.
Perfusion. 2002;17(5):391-4.
Judd WJ. How I manage cold agglutinins. Transfusion 2006;46:324-326.
Literature 3.8.1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Duguesnoy RJ, Anderson AJ, Tomasulo PA, Aster RH. ABO compatibility and platelet
transfusions of alloimmunized thrombocytopenic patients. Blood 1979;54:595-9.
Lee EJ, Schiffer CA. ABO compatibility can influence the results of platelet transfusion.
Results of a randomised trial. Transfusion 1989;29:384-9.
Lozano M, Cid J. The clinical implications of platelet transfusions associated with ABO or
Rh(D) incompatibility. Transfus Med Rev 2003;17:57-68.
Ogasawara K, Ueki J, Takenaka M, Furihata K. Study on the expression of ABH antigens on
platelets. Blood 1993;82:993-9.
Shehata N,Tinmouth A, Naglie G, Freedman J, Kumanan W. Transfusion 2009 EV.
Skogen B, Rossebo B, Husebekk A, Havnes T, Hannestad K Minimal expression of
bloodgroup A antigens on trombocytes from A2 individuals Transfusion 1988: 28, 456
Brand A, Sintnicolaas K, Claas FH, Eernisse JG. ABH antibodies causing platelet transfusion
refractoriness. Transfusion 1986;26:463-6.
Heal JM, Rowe JM, McMican A, Masel D, Finke C, Blumberg N. The role of ABO matching in
platelet transfusions. Eur J Haematol 1993; 50: 110-7
Julmy F, Ammann RA, Taleghani BM, Fontana S, Hirt A, Leibundgut K. Transfusion efficacy
of ABO major-mismatched platelets (PLTs) in children is inerior to that of ABO-identical PTLs.
Transfusion 2009; 49: 21-33
Lee EJ, Schiffer CA. ABO compatibility can influence the results of platelet transfusion.
Results of a randomized trial. Transfusion 1989;29:384-9.
105
11.
12.
13.
14.
15.
16.
17.
18.
19.
Literature 3.8.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
Literature 3.9
106
1.
2.
Shanwell A, Andersson TM, Rostgaard K, Edgren G, Hjalgrim H, Norda R, et al. Posttransfusion mortality among recipients of ABO-compatible but non-identical plasma. Vox Sang
2009 ;96:316-23.
Vrielink H, PF v.d. Meer. Collection of white blood cell-reduced plasma by apheresis.
Transfusion 2004; 44:917-923.
107
4.1
The Hb does not need to be increased as long as the usual reserves and compensation
mechanisms are sufficient to meet the oxygen demands of the tissues. However, when
oxygen demand threatens to exceed supply, it is necessary to administer erythrocytes.
The decision to give a blood transfusion to a patient with chronic anaemia is based on the
patients symptoms that indicate a lack of oxygen-transport capacity and a number of clinical
108
parameters such as patient age, the speed at which the anaemia occurred, the cause of the
anaemia, cardiac and/or pulmonary disease resulting in decreased oxygen reserves and/or
the ability to compensate for the lack of oxygen transport capacity. The Hb can also be
included in this.
Research has shown that a low Hb is often tolerated well. In 32 healthy, resting
volunteers,undergoing acute iso-volemic haemodilution to an Hb of 3 mmol/L an adequate
oxygen supply was maintained (Weiskopf 1998). In 134 adult Jehovahs Witnesses with an
Hb < 5 mmol/L, deaths due to anaemia only increased at an Hb below 3 mmol/L (Viele
1994).
Other considerations
Recently, a number of studies have been published that show that pre-operative anaemia is
a risk factor for post-operative mortality.
Please refer to the CBO guideline The pre-operative course, 2010 (www.cbo.nl), for
recommendations on treatment of pre-operative anaemia.
The following recommendations are not evidence-based, but are based on expert opinion
(opinion of the working group) and international guidelines.
Recommendations 4.1
1.
2.
3.
4.
5.
The only indication for a therapeutic erythrocyte transfusion in the case of chronic
anaemia is a symptomatic anaemia*.
An Hb < 3 mmol/L is an absolute indication for an erythrocyte transfusion.
Prophylactic erythrocyte transfusions can be indicated for asymptomatic chronic
anaemia in a patient without cardio-pulmonary limitations and an Hb < 4 mmol/L.
Prophylactic erythrocyte transfusions can be indicated in the case of limited cardiopulmonary compensation abilities or risk factors in accordance with table 5.2, lines 4,
5 and 6, in Chapter 5.
If there are no obvious limited cardio-pulmonary compensation abilities or risk factors,
the following Hb triggers can be maintained for prophylactic erythrocyte transfusions
for chronic anaemia:
Age (years)
Hb trigger (mmol/L)
< 25
3.5- 4.5
25-50
4.0 -5.0
50-70
5.5
> 70
6.0
109
4.2
Production disorders
110
Conclusions 4.2.1
Anaemias caused by nutritional deficiency only form an indication for blood
transfusion at extremely low Hb levels.
Level 4
D
Level 2
Expert opinion
Recommendations 4.2.1
1.
2.
Anaemia caused by iron deficiency does not form an indication for transfusion,
unless the severity of the anaemia reaches the absolute transfusion indication (HB <
3 mmol/L) or if hypoxic symptoms occur at rest.
In patients undergoing elective, major surgical procedures it is recommended to treat
any iron-deficiency anaemia for a minimum of four weeks prior to surgery.
111
Other considerations
A separate point of discussion is whether or not allogeneic transfusions can inhibit the
patients immunity against tumours and thereby promote relapse of the cancer after surgical
treatment that should be curative (see Chapter 7.2.12).
Recommendation 4.2.2
Randomised study of the relationship between anaemia and any decreased efficacy of
chemotherapy / radiotherapy is desirable.
Lymphatic malignancies
Approximately 70% of patients with multiple myeloma (MM) and approximately 25% of
patients with non-Hodgkins lymphoma develop anaemia during treatment.
Patients with chronic lymphatic leukaemia (CLL) can develop anaemia due to autoantibodies
(immune haemolysis (AIHA), see paragraph 4.4.5), by suppression of erythropoiesis or by
chemotherapy. Patients with immune-mediated haemolysis are treated according to the
protocols that have been developed for patients with idiopathic AIHA (see paragraph 4.4.5).
If anaemia is the result of bone marrow suppression, it will improve upon response to
treatment. No studies of Hb triggers for transfusion have been performed for this condition.
Recommendation 4.2.2
1.
112
Liumbruno 2009
TA-GvHD has never been reported in HIV infected patients, despite the
administration of not irradiated blood components.
Level 3
C
D
Collier 2001
SHOT-rapporten 1996-2009
113
Level 3
Gasche 1997
Recommendations 4.2.4
1.
2.
3.
114
Conclusions 4.2.5
Parvo-B19 infection during the first term of pregnancy
approximately 10% intra-uterine death due to hydrops.
Level 3
C
Level 4
Tolfvenstam 2001
Level 3
causes
The aim of iron suppletion during pregnancy is to achieve a ferritin level >
80 g/L.
C
Elion-Gerritzen 2001
Other considerations
There are many similarities in the guideline for transfusion to pregnant women, but there is
very little scientific evidence to support it.Therefore one may conclude that the precautionary
principle isleading.
Recommendations 4.2.5
1.
2.
3.
4.
The need for a transfusion during pregnancy should be considered per individual
patient, depending on underlying disease and the health of the foetus.
Iron supplementation can be considered for iron-deficiency anaemia in pregnancy.
Parvo-B19 safe transfusions are recommended for sero-negative pregnant women
(see Chapter 2.2.6).
A woman of (pre) fertile age should receive cEK compatible erythrocyte transfusions
(see also Chapter 3.7.1).
115
mL is recommended in children (Rowley 2000). The height of the IgG/IgM titre has not been
standardised between the various centres. In the case of major ABO incompatibility, the isoagglutinins of the recipient can persist until after day 200 (Herschko 1980) and the titre can
still rise during the first three weeks after transplantation (Sniecinski 1988, Ochelford 1982).
In addition to delayed haemolytic reactions, complications include prolonged aplasia and
pure red cell aplasia (Fitzgerald 1999, Salmon 1999, Lyding 1999, Laurencet 1997, OzielTaleb 1997, Bornhauser 1997, Moog 1997, Toren 1996, Greeno 1996, Lopez 1994,
Sniecinski 1988, Hows 1986, Warkentin 1983).
Haemolysis due to minor ABO incompatibility
In the case of minor ABO incompatibility, some centres recommend the removal of plasma if
the donor has an IgG and/or IgM titre 128. The consensus by Socit Franaise de Greffe
de Moelle even recommends washing of the transplant at a titre > 32. A good compromise is
plasma reduction at a titre > 32 (Rowley 2000, Lapierre 2000).
Anti-A/anti-B antibodies from the donor can also be stimulated by (tissue) expression of
blood group A and/or B in the patient. Prospective follow-up shows that approximately 25%
of the recipients develop a positive DAT during the first 3 weeks after bone marrow
transplantation (BMT) / peripheral blood stem cell transplantation (PBSC) (Lapierre 2000,
Rowley 2000, Hows 1997).
Passenger B-cells in the transplant are usually stimulated after 7 14 days. The antibody
production usually extinguishes several weeks after transplantation. Life threatening
haemolysis has been described between day 5 and day 14 after transplantation in
particular after non-myelo-ablative conditioning and PBSC in which the entire circulating
RBC volume of the recipient is broken down in 1 3 days (Lapierre 2000, Bolan 2001,
Salmon 1999, Hows 1997, Laurencet 1997, Oziel-Taleb 1997, Toren 1996, Greeno 1996,
Lopez 1994, Gajewski 1992, Warkentin 1983), as are compatible donor transfusions as
innocent bystander.
Non-ABO blood group specific antibodies
These can come from the donor or the recipient and are targeted against the stem cell
donor, the recipient or the blood donor. Multiple specificities such as D, c, Cw, e, E, Jka and
Le have been found (Lapierre 2001, Bornhauser 1997, Godder 1997, Lopez 1994).
A randomised study revealed that irregular antibodies formed more frequently after PBSC
(3/21) than after BMT (0/28) (Lapierre 2001). The identification of the specificity is easier if
the pre-transplant erythrocyte typing of donor and recipient is known.
Non-specific autoantibodies
These can occur > 2 years after transplantation, in association with immune deficiency, CMV
infection, unrelated donors and GvHD. The frequency is approximately 4% (Sanz 2007). As
a rule, the autoantibody formation is self-limiting if immunological recovery is achieved,
although the condition is fatal in 50% of patients due to haemolysis, multi-organ failure or
refractory thrombocytopenia (Horn 1999, Chen 1997, Drobyski 1996, Lord 1996).
116
Conclusions 4.2.6
Every centre has developed its own empirical method for
preventing/reducing haemolytic reactions with stem cell / bone marrow
transplants. In adults the RBC volume is usually reduced to < 15 mL, if the
patient has an IgG and/or IgM titre > 16, in combination with slow
Level 3
administration and good hydration of the patient. In children, the RBC
volume is reduced to < 10 mL.
C
Level 3
Level 3
Labar 2000
Other considerations
The working group members are of the opinion that it is important to have access to
complete pre-transplantation data if possible, also in the case of a non-related donor due to
post-transplantation haemolysis.
In order to prevent antibody-mediated haemolysis of erythrocytes it is recommended to
transfuse with either O erythrocytes or erythrocytes that are compatible with donor and
recipient in case of minor and major blood group antagonism.
117
In France, national protocols are maintained and evaluated for the transfusion policy after
transplantation. It would be desirable to achieve the same in the Netherlands.
Recommendations 4.2.6
1.
2.
3.
4.
5.
4.3
118
the quality of life or survival. Based on these results, general use of EPO is however not
recommended (Marec-Berard 2009).
The use of EPO resulted in a statistically significant reduction in the percentage of patients
needing transfusion, but the decrease in the number of erythrocyte concentrates (EC)
administered was relatively small. For the dosage and duration of administration used in
these studies, EPO resulted in a reduction of 1 unit of EC or less. In 2002 a working group
from the American Society for Haematology (ASH) and the American Society of Clinical
Oncology (ASCO) released guidelines for the clinical practitioner that are based on 22
randomised studies, six of which were performed in a double-blind manner. The advice is to
consider EPO, at the lowest possible dosage, when the Hb concentration is < 6.2 mmol/L
(Rizzo 2002, 2010). The guideline from the 'European Organisation for Research and
Treatment of Cancer' (EORTC) focuses on the use of ESAs in patients with cancer who are
being treated with chemotherapy and/or radiotherapy (Bokemeyer 2007). The guideline is
based on 43 studies. A lower requirement for blood transfusion (up to 20% compared to
control individuals) is reported in 29 studies of chemotherapy, with four studies being
randomised and double-blind. The quality of life was examined in 35 studies, of which three
were randomised and double-blind. These three studies found an improvement of undefined
magnitude in the haemoglobin level with EPO (epoietin alpha or recombinant human
erythropoietin). No difference in mortality was found in six studies in which this was reported.
No randomised, double-blind study of the transfusion requirements and quality of life has
been performed for patients receiving radiotherapy.
A randomised study is necessary to be able to make definitive conclusions about the quality
of life, blood conservation and cost efficacy by erythropoietin, with a similar Hb as a target
value in both arms of the study group.
Conclusions 4.3.1
The erythropoiesis stimulating agents (ESAs) significantly reduce the need
for blood transfusions in patients with chemotherapy-associated anaemia
due to solid tumours or haematological malignancies compared to the
Level 1
control treatment consisting of a placebo or no erythropoietic growth factor
(RR 0.64 (0.60 0.68)).
A1
Level 1
119
Level 4
Recommendations 4.3.1
1.
2.
3.
Erythropoiesis stimulating agents (ESAs) should only be used for the treatment of
patients with chemotherapy-induced anaemia due to cancer with the aim of saving on
blood transfusions (see also recommendation 1 under 4.3.2).
The treating doctor should discuss the potential dangers (thrombosis, decreased
survival time) and benefits (fewer transfusions) of ESAs and the potential dangers
(severe infections, immunological side effects) and benefits (rapid increase in Hb) of
blood transfusions with the patient.
The use of EPO in patients with cancer for indications other than the treatment of
chemotherapy-induced anaemia is not recommended.
4.3.2 The effects of ESAs on mortality and survival of patients with cancer
It has been demonstrated that EPO in patients with solid tumours and chemotherapyinduced anaemia reduces the need for transfusions and also reduces the number of units
that need to be administered. However, it has also been shown that EPO increases the risk
of thrombo-embolic complications (Bohlius 2006). It is not clear whether and how EPO
influences the response of the cancer to therapy and what the long-term consequences are.
Scientific support
A search was performed for systematic reviews of RCTs into the effect on mortality and
long-term survival in EPO-treated patients.
A Cochrane review from 2006 showed that EPO reduced the need for transfusion (Relative
Risk = RR 0.64; CI 0.60 0.68; 42 trials, N = 6510), but the risk of thrombo-embolic
complications increased (RR 1.67; CI 1.35 2.06; 22 trials; n 6769). There was uncertainty
about the effect on survival (HR 1.08; 95% CI 0.99 1.18) (Bohlius, 2006).
A very recent meta-analysis based on data from individual patients showed that mortality
was elevated both during the active study period (Hazard Ratio = HR 1.17; CI 1.06,1.30) and
in the long term (HR 1.06; CI 1.00, 1.12). This effect was less pronounced for patients
treated with chemotherapy: HR mortality in study period 1.10; CI 0.98 1.24 and HR longterm survival 1.04; CI 0.97 1.11. However, the test for interaction between EPO and
chemotherapy on survival was not significant (p = 0.42), indicating a similar effect as in the
total group of patients (Bohlius, 2009), but it should be noted that chemotherapy-induced
anaemia has a different origin and therefore cannot be compared directly to the total group
of cancer patients with anaemia that is not caused by chemotherapy.
120
Conclusion 4.3.2
Use of EPO in cancer patients increases mortality by approximately 17%
(6% - 30%) and also decreases survival after 6 months. Chemotherapytreated cancer patients with anaemia had an increased risk of mortality of
Level 1
10%, and a decreased long-term survival.
A1
Bohlius 2009
Other considerations
In view of the fact that the favourable effects of EPO have, to date, only been demonstrated
in adult patients with solid tumours and chemotherapy-associated anaemia (see 4.2.1 and
4.2.3) and the fact that the increase in mortality has also been demonstrated in patients with
cancer not receiving chemotherapy (this paragraph: 4.2.2), the working group is of the
opinion that there is only an indication for the use of EPO in patients with solid tumours and
chemotherapy-induced anaemia.
Recommendations 4.3.2
1.
2.
The therapeutic indication for EPO should be strictly adhered to. In other words,
treatment with EPO is only indicated in adult patients with chemotherapy-induced
anaemia with a non-myeloid malignancy. The starting Hb should be 6.2 mmol/L
and the target Hb 6.2 7.4 mmol/L.
The treatment with EPO should be stopped at an Hb > 8.2 mmol/L.
Bohlius, systematic
2009
review;
individual
patient data
metaanalysis
A1 search,
selection,
quality
evaluation,
analysis +
13933
cancer 21 63000 IU*
patients
EPO/week for
from 53 trials
8-52
weeks;
median followup 6.2 months;
active
study
period
3.7
months
Results
Risk of thrombo-embolic
complications was
elevated (RR 1.67; 95% CI
1.35 2.06; 35 trials;
n=6769)
Uncertainty about the
effect on survival (HR
1.08; 95% CI 0.99 1.18;
42 trials, n=8167)
EPO increased mortality
during active study period
(HR 1.17; 95% CI 1.06
1.30) and decreased
survival (HR 1.06; CI 1.00
1.12). For
chemotherapy-treated
patients, the HR was HR
1.10; CI 0.98 1.24 and
for the survival 1.04; 95%
CI 0.97 1.11. interaction:
p = 0.42
121
4.3.3 The use of erythropoiesis stimulating agents (ESAs) for myeloid conditions
There has been limited evidence with respect to the effect of ESAs on myeloid conditions
due to the possible risk of stimulating the growth of malignant cells. Cases have also been
reported about complications due to ESAs, such as splenomegaly and splenic infarction due
to extra-medullary myelopoiesis (Cazzola 1992, Iki 1991, Motoji 1990).
Most of the experience with ESAs has now been gained from myelodysplasias. In 11 phase I
or II studies, a total of 382 patients were treated with 75 to 3,000 U/kg/week (Cazzola 1996,
Rose 1995, Musto 1995, Isnard 1994, Goy 1993, Aloe Spiriti 1993, Stenke 1993, Zeigler
1993, Ludwig 1993, Shapiro 1993, Jones 1992). An improvement in Hb was found in 13.6%
of the patients, particularly those with refractory anaemia or refractory anaemia with ring
sideroblasts. Only 6% of the patients who previously required transfusions became
independent of transfusions. Hellstrom-Lindberg (1995) confirmed that only a small portion
of the total group of patients with MDS treated with EPO showed a favourable effect. Only
one randomised, placebo-controlled study with 87 patients has been performed (Italian MDS
Study Group 1998). In this study, the Hb of (60% of the) patients with non-transfusiondependent myelodysplasia (mainly refractory anaemia and refractory anaemia with
sideroblasts) improved due to ESAs; the percentage of transfused patients remained the
same in both groups. To summarise, it can be said that the administration of an ESA for this
condition only results in an increase in Hb concentration and a decrease in the need for
transfusion for a minority of patients (Rizzo 2002). However, the endogenous epoietin level
and the transfusion history can be used to select patients who have a greater chance of a
good response to ESAs (Hellstrom et al, Brit J. of Hematology 120: 1037 -1046).
Conclusion 4.3.3
The treatment of all myelodysplasia patients with an erythropoiesis
stimulating agent (ESA) has only a slight (< 10%) effect on the transfusion
need of transfusion-dependent patients. Selected patients, with an EPO
level < 500 U/ml are more likely to respond to treatment with an ESA.
Level 2
A2
Italian MDS study group 1998
B
Rizzo 2002, Hellstrom-Lindberg 1995, 1997, 2003
C
Rose 1995, Musto 1995, Isnard 1994, Goy 1993, Alow Spiriti 1993;
Stenke 1993, Zeigler 1993, Ludwig 1993, Shapiro 1993, Jones 1992
Other considerations
There are no curative treatment options for older patients with myelodysplasia. The
identification of patients with a potentially favourable response to ESAs in combination with
GM-CSF or not is of great importance (Thompson 2000).
Recommendations 4.3.3
1.
2.
122
EPO is not recommended for the treatment of patients with myelodysplasia with a
high (> 500 mg/L) endogenous EPO level.
Research into the identification of responders to EPO is desirable, in order to assign
EPO a possible role in the treatment of myelodysplasia patients.
Level 3
123
Level 2
For patients with Inflammatory Bowel Disease (IBD) who do not respond
sufficiently to iron supplementation, the administration of ESA results in a
significant increase in Hb and an improvement of the quality of life with less
fatigue.
B
Other considerations
In the case of anaemia due to chronic illness such as rheumatoid arthritis, HIV and IBD,
there is a relative shortage of erythropoietin and inhibition of erythropoiesis by proinflammatory cytokinins, such as TNF-alpha and interferon. Both factors are corrected by
ESAs. The increase in Hb caused by ESAs is much greater than the target value with
transfusions, EPO does not result in relevant transfusion savings for rheumatoid arthritis and
IBD.
Recommendations 4.3.5
1.
2.
3.
EPO is not yet a generally accepted indication for anaemia due to rheumatoid
arthritis or inflammatory bowel disease (IBD).
In the case of HIV infection, the endogenous erythropoietin level should be included
in the decision to treat with erythropoiesis stimulating agents (ESAs). Studies show
that responders have erythropoietin levels < 500 mg/L.
In the case of HIV infection with anaemia, the position of EPO in relation to a
relatively low erythropoietin level should be examined further.
124
Recommendation 4.3.6
The use of erythropoiesis stimulating agents (ESAs) is not recommended as a supportive
therapy for severe aplastic anaemia.
4.4
Breakdown disorders
125
observational study revealed that more than 75% of children with sickle cell disease and a
Parvo B19 infection require a transfusion (Smith-Whitley 2004).
Threatened anaemia due to acute liver and/or spleen sequestration
Acute liver and/or spleen sequestration usually occurs in early childhood and is a rapidly
developing and potentially fatal complication. In these cases the blood is withdrawn from the
circulation, which results in acute severe anaemia, hypovolaemia and rapid progressive
splenomegaly. Transfusions are recommended in symptomatic cases of acute sequestration
and it should be taken into consideration that a portion of the erythrocytes will return to the
circulation after sequestration, which can cause a rapid increase in Hb with associated
hyperviscosity (Ohene-Frempong 2001, Josephson 2007, Wahl 2009).
Threatened anaemia due to haemolytic crisis
Infections whether viral, bacterial or parasitic (e.g. malaria) in nature can result in an
acute increase in haemolysis (haemolytic crisis). Acute blood transfusion can be indicated in
order to treat or prevent cardiac decompensation (Wanko 2005).
Conclusions 4.4.1.1
Acute blood transfusion is only indicated in patients with sickle cell disease
for (impending) cardiac or respiratory symptoms. There is no specific Hb
trigger for administering a blood transfusion, but patients should not be
Level 3
transfused at an Hb over 6.5 mmol/L due to hyperviscosity.
C
D
Level 4
Level 3
Alexy 2006
Josephson 2007, Wahl 2009
Smith-Whitley 2004
Recommendations 4.4.1.1
1.
126
Blood transfusions are indicated in patients with sickle cell disease if cardiac or
respiratory symptoms develop as a result of anaemia. There is no specific Hb trigger
at which transfusions must be given.
2.
When giving a blood transfusion to patients with sickle cell disease, one must ensure
that the Hb remains < 6.5 mmol/L in order to prevent hyperviscosity.
Level 4
Josephson 2007
Recommendation 4.4.1.2
It is adviced to treat patients with sickle cell disease and an acute chest syndrome with a
blood transfusion. Exchange transfusions are recommended for severe hypoxaemia (pO2 <
60 mmHg in adults and pO2 < 70 mmHg in children), the aim being to achieve an HbS% <
30%.
127
acute treatment of children with an acute CVA showed that an exchange transfusion as
initial treatment was more effective in preventing a second CVA than a normal transfusion
(Hulbert 2006). Despite the absence of comparative studies between transfusing or not, all
experts are of the opinion that an acute CVA is an absolute indication for transfusion
(Charache 1992, Ohene-Frempong 1991). Based on the above-mentioned study by Hubert
et al, the advice is to perform an exchange transfusion to decrease the HbS to < 30%
(Charache 1992, Ohene-Frempong 1991, Hulbert 2006).
Conclusion 4.4.1.3
In the event of an acute CVA, the advice is to perform an exchange
transfusion immediately, aiming to achieve an HbS% < 30%.
Level 3
B
Hulbert 2006
D
Charache 1992; Ohene-Frempong 1991
Recommendation 4.4.1.3
In patients with sickle cell disease and an acute CVA, the advice is to perform an exchange
transfusion immediately, aiming to achieve an HbS% < 30%.
Hassell 1994
Recommendation 4.4.1.4
Sickle cell patients with multi-organ failure defined as severe organ failure of at least two
organ systems in the setting of a vaso-occlusive crisis should undergo an exchange
transfusion.
4.4.1.5 Priapism
Priapism is defined as an involuntary erection without sexual stimulation that persists for at
least 4 hours. Priapism occurs frequently with sickle cell disease, particularly during puberty.
128
Persistent priapism is painful and can lead to structural erectile dysfunction and must be
viewed as a medically urgent complication. There is ongoing debate about whether acute
blood transfusion can play a role in the treatment of acute priapism by reducing the HbS%. A
meta-analysis was published in 2006 on all clinical studies and case reports about the
treatment of priapism in which no difference was found in the duration until symptoms
disappeared (Merritt 2006).
Conclusion 4.4.1.5
There is no indication for (exchange) transfusion as a treatment for
priapism.
Level 3
B
Merritt 2006
Recommendation 4.4.1.5
There is no indication for (exchange) transfusion in the acute treatment of priapism.
4.4.1.6 Acute painful (vaso-occlusive) crisis
There is no indication for acute transfusion or exchange transfusion for an uncomplicated
vaso-occlusive crisis. In fact, an observational study (Platt 1991) revealed a positive
correlation between the level of Hb and the occurrence of a vaso-occlusive crisis, probably
due to the increased viscosity. There are no data on the efficacy of exchange transfusions
for an acute sickle cell crisis. Experts indicate in various reviews that an acute painful crisis
is not an indication for (exchange) transfusion (Josephson 2007, Ohene-Frempong 2001).
Conclusion 4.4.1.6
There are no arguments for transfusion during acute painful crises.
Level 4
D
Ohene-Frempong 2001, Josephson 2007
Recommendation 4.4.1.6
There is no indication for performing (exchange) transfusions for the treatment of an acute
painful crisis in patients with sickle cell disease.
4.4.2 Elective indications for blood transfusion in patients with sickle cell disease
4.4.2.1 Pre-operative preparation in patients with sickle cell disease
There is much discussion about the need to perform exchange transfusions prior to surgery
(in order to reduce the HbS%). A prospective, randomised, multi-centre study of patients
with sickle cell disease undergoing mainly gall bladder, ENT and orthopaedic surgery in
which an aggressive (target HbS < 31%) pre-operative transfusion policy was compared to a
conservative on top of transfusion (target Hb of 6.2 mmol/L) transfusion policy showed
that the frequency of post-operative complications and acute chest syndrome was the same
for both groups, but that twice the number of complications due to the transfusion occurred
in the group with the aggressive pre-operative transfusion policy (Vichinsky 1995). This
study did not examine whether the complete omission of prophylactic transfusions was also
justified. As far as HbSC (double heterozygous sickle cell disease) is concerned, there are
129
two retrospective studies that both show a strongly reduced incidence of sickle cell related
complications in patients who received a pre-operative blood transfusion versus patients
who did not receive a transfusion (Koshy 1995, Neumayr 1998). It is important to mention
that various experts advise that the Hb concentration should not exceed 6.5 mmol/L in order
to prevent hyperviscosity (Vichinsky 2001, Ohene-Frempong 2001). No randomised studies,
however, have been performed on this matter. Mainly patients with HbSC sickle cell disease
and a relatively high risk of post-operative complications (abdominal surgery) appeared to
benefit greatly from pre-operative blood transfusion (0% versus 35% complications)
(Neumayr 1998).
Conclusions 4.4.2.1
There is no prospective comparative study on the value of blood
transfusion as pre-operative preparation for sickle cell patients. A
prospective randomised study revealed no difference in post-operative
Level 2
complications between an aggressive transfusion policy and an on top of
transfusion policy.
A2
Level 3
Vichinsky 1995
For patients with double heterozygous sickle cell disease (HbSC), two
large retrospective studies have shown a lower incidence of sickle cell
related complications in patients undergoing an elective surgical procedure
when they were transfused preoperatively. The authors advise that the Hb
in this patient group should not be allowed to exceed 6.5 mmol/L.
C
D
Recommendation 4.4.2.1
Despite the lack of prospective randomised studies, the administration of pre-operatieve
blood transfusions to a maximum Hb of 6.5 mmol/L should be considered for sickle cell
patients undergoing surgery with an intermediate risk (abdominal surgery such as
cholecystectomy, Caesarian section, appendectomy, splenectomy or extensive orthopaedic
surgery.).
4.4.2.2 Pregnancy in patients with sickle cell disease
Sickle cell disease causes an increased risk of maternal and foetal death. A randomised,
prospective study from 1988 on the effect of prophylactic transfusions during pregnancy in
sickle cell disease showed that mortality of both mother and child in the treatment group
was the same as for the group that did not receive transfusion. However, a significant
reduction in painful crises was observed in the group that received prophylactic transfusions
(Koshy 1988).
Based on these benefits concerning sickle cell related complications such as vaso-occlusive
crises, experts advise that prophylactic blood transfusions should only be considered for a
pregnancy with an increased risk of complications, such as a multiple pregnancy and
pregnancies in women with a history of perinatal mortality (Wayne 1995, Koshy 1995).
130
Conclusions 4.4.2.2
There is no indication for the prophylactic transfusion of pregnant women
with sickle cell disease.
Level 2
A2
Level 4
Koshy 1988
Recommendation 4.4.2.2
There is no indication for prophylactic transfusion of patients with sickle cell disease during
pregnancy. Prophylactic transfusions can be considered only in sickle cell patients with an
increased risk of complications, such as women with multiple pregnancies or a history of
perinatal mortality.
4.4.2.3 Chronic transfusion policy in patients with sickle cell disease
131
these patients. Therefore, silent infarctions do not form an indication for chronic blood
transfusion.
Conclusions 4.4.2.3.1
Children with an increased risk of CVA defined as a cerebral blood flow
speed > 200 m/s using transcranial Doppler have an indication for
Level 2
chronic blood transfusion with a target HbS of < 30%.
A2
Adams 1998
Level 2
Level 4
Adams 2005
Wang 1991, Wilmas 1980
Ohene-Frempong 2001
Recommendations 4.4.2.3.1
1.
Children with sickle cell disease and an increased risk of a CVA defined as an
elevated flow rate of the cerebral blood vessels of > 200 m/s confirmed using
transcranial Doppler or with a history of CVA have an indication for chronic
transfusion policy with a target HbS of < 30%.
2.
For children with an increased risk of CVA or a history of CVA, the chronic
transfusion policy should be continued at least until reaching adulthood.
3.
Once adulthood has been reached, cessation or reduction of the intensity can be
considered, provided that the patient has been neurologically stable for at least 4
years.
4.4.2.3.2 Prevention of acute chest syndrome (ACS)
The acute chest syndrome (ACS) is a potentially fatal complication of sickle cell disease.
The treatment of choice in the prevention of a recurring ACS in patients with sickle cell
disease is hydroxy urea. For patients with recurrent episodes of ACS despite hydroxy urea,
132
a chronic (exchange) transfusion schedule is advised with a target HbS of < 50%. A
retrospective study showed a strong reduction in the incidence of ACS in patients with sickle
cell disease who received chronic transfusion therapy (Hankins 2005). An earlier prospective
study of the effects of chronic blood transfusion on the incidence of CVAs in a high risk
population of children with sickle cell disease also showed a strong reduction in the number
of episodes of ACS (Miller 2001). It should be noted that this last study though prospective
in nature was not primarily designed for this query.
Conclusions 4.4.2.3.2
In patients with a recurring acute chest syndrome (ACS) under hydroxy
urea, a chronic transfusion policy with a target HbS of < 50% can be
considered. The efficacy of chronic transfusion for the prevention of ACS
Level 3
was observed in a comparative study on the effect of chronic transfusion
in the prevention of CVAs in children with sickle cell disease.
B
Level 3
Miller 2001
Hankins 2005
Recommendation 4.4.2.3.2
A chronic (exchange) transfusion with a target HbS of < 50% can be considered in patients
with sickle cell disease with recurring acute chest syndrome (ACS) despite treatment with
hydroxy urea.
133
Level 3
Charache 1995
Miller 2001
Koshy 1988
Recommendation 4.4.2.3.3
A chronic transfusion policy for the prevention of frequent recurring vaso-occlusive crises
without response to hydroxy urea can be considered for patients with sickle cell disease.
Despite the proven efficacy, the negative consequences of a chronic transfusion policy (alloimmunisation, iron accumulation and the risk of transmission of infectious diseases) for this
indication should be included in the decision-making process before implementing chronic
blood transfusions.
4.4.2.4 Complications of chronic blood transfusion in patients with sickle cell disease
4.4.2.4.1 Allo-immunisation
See Chapter 3.7.2.
134
Recommendation 4.4.2.4.3
For patients with sickle cell anaemia who are Parvo B19 IgG negative, a Parvo B19 negative
blood component is recommended for the prevention of an aplastic crisis (see also Chapter
2.2.6).
4.4.3 Congenital breakdown disorder: homozygous beta thalassaemia
Beta thalassaemia is an autosomal recessive disorder of the haemoglobin production.
Several mutations and deletions of the globin gene have been described, which result in a
complete or partial deficiency of globin chains resulting in an excess of globin chains.
The excessive number of globin chains results in ineffective erythropoiesis and this in turn
results in severe anaemia and compensatory erythroid hyperplasia in the bone marrow
(Olivieri 1999). This pathology is most pronounced in homozygous beta 0 thalassaemia, in
which a transfusion indication occurs at a very early age. Intermediate thalassaemia results
in a marked decrease in beta globin production, which can result in clinical symptoms in
some of the patients and results in a transfusion indication in some cases. Iron accumulation
due to increased absorption form the bowel can occur in patients with intermediate
thalassaemia without a transfusion indication.
The decision to start regular blood transfusions for beta thalassaemia is based on the
severity of the symptoms of anaemia and bone marrow expansion. Early implementation of
transfusions appears to reduce the frequency of allo-immunisation. The UK guideline
advises to start transfusing before the age of three (UK Thalassaemia society 2008).
Chronic transfusion therapy with a target Hb of 5.6 6.2 mmol/L results in an
improvement of the clinical course of homozygous beta thalassaemia, suppression of the
erythroid bone marrow expansion and less iron accumulation than a hypertransfusion
schedule with a target Hb of 6.2 7.4 mmol/L (Cazzola 1997). Adequate chelation therapy
results in a significantly better life expectancy and less secondary organ damage in patients
with beta thalassaemia with a chronic transfusion indication (Brittenham 1994). Patients with
an average serum ferritin concentration < 2500 g/L had significantly less heart failure than
patients with a higher average ferritin (Borgna-Pignatti 2004).
Patients with homozygous beta thalassaemia can be cured using allogeneic stem cell
transplantation, which should preferably be performed at the youngest possible age. Various
transplant studies all over the world have now achieved thalassaemia-free survival
percentages of between 85 and 90% and a long-term survival of 76 100% depending on
the age and risk factors, such as liver fibrosis and iron accumulation (Robberts 1997, Di
Bartolomeo 1997, Boulad 1998, Lawson 2003).
135
Conclusions 4.4.3
For patients with homozygous beta thalassaemia, chronic blood
transfusion with a target Hb of 5.6 6.2 mmol/L results in a good clinical
improvement and less iron accumulation than with a hypertransfusion
Level 3
schedule with a target Hb of 6.2 7.4 mmol/L.
B
Level 2
Level 2
Cazzola 1997
Recommendations 4.4.3
1.
2.
3.
The clinical symptoms of anaemia and bone marrow expansion are the basis of the
decision to start a chronic transfusion policy in patients with homozygous beta
thalassaemia or intermediate thalassaemia.
A target Hb of 5.4 6.2 mmol/L is recommended for chronic transfusion therapy for
beta thalassaemia patients.
A chronic transfusion policy in beta thalassaemia patients should be complemented
by adequate chelation therapy with a target average ferritin level < 2500 g/L. This
prevents heart failure and organ damage due to iron accumulation.
136
The diagnosis PNH can be confirmed by means of flow cytometry by which both normal and
PNH cells can be detected. In addition to flow cytometry, a small population of PNH cells can
also be detected using fluorescent pro-aerolysin (Brodsky 2000).
The treatment depends on the type of PNH. In the case of hypoplastic PNH with severe
aplastic anaemia an allogeneic bone marrow transplant is a potentially curative treatment; in
some cases, immunotherapy is given first in the form of anti-thymocyte globulin and
cyclosporine. Haemolysis and thrombosis are foremost in classic PNH. In the past an
allogeneic bone marrow transplant was the only effective therapy for these patients, but
recently eculizumab has been proven to be effective in the treatment of haemolysis due to
classic PNH (Hillmen 2004, Hillmen 2006, Brodsky 2008).
Eculizumab is a humanised monoclonal antibody against the complement protein C5 that
inhibits complement activation. The first pilot study of 11 classic PNH patients showed that
eculizumab is able to reduce haemolysis and the need for transfusion: the average need for
transfusion dropped from 1.8 to 0 units per month (Hillmen 2004). A randomised doubleblind placebo-controlled study (the TRIUMPH study) in 87 patients with classic PNH showed
a reduction in the number of transfused units from 10 to 0 in the eculizumab arm: 51% of the
patients treated with eculizumab became transfusion-free (Hillmen 2006). The SHEPHERD
study in 79 classic PNH patients showed that eculizumab improved the haemolysis in 87%
of the patients, reduced the need for transfusion by 52% (from 12.3 to 5.9 units per patient)
and there was a complete absence in the need for transfusion in 51% of the patients
(Brodsky 2008). In addition, it appears that the long-term use of eculizumab reduces the risk
of thrombotic complications from 7.4 to 1.1 events per 100 patient years (Hillmen 2007).
No Hb trigger is mentioned for transfusion indication in the literature.
There is no contra-indication for plasma (containing blood components) and no indication for
washed erythrocytes (Brecher 1998, Fitzgerald 1994, Sirchia 1990).
Conclusions 4.4.4
Studies show that eculizumab reduces the need for transfusion in patients
with classic transfusion-dependent PNH.
Level 1
A2
Level 2
Level 2
Brodsky 2008
137
Recommendations 4.4.4
1.
2.
3.
138
139
Both the requesting doctor and the responsible people in the laboratory should realise that
transfusion must take place for vital indications, despite compatibility problems and positive
cross matches (Salama 1992, Petz 1980, Jefferies 1994, Garraty 1993).
Recommendations 4.4.5
1. The suspicion of auto-immune haemolytic anaemia (AIHA) should be stated with the
request for diagnosis and transfusion.
2. In the case of auto-immune haemolytic anaemia (AIHA) in the acute phase, urgent
diagnosis is often indicated for determining the type and specificity of antibodies and
the exclusion of alloantibodies (see also Chapter 3.7.3).
3. For a new patient, the specificity of the autoantibodies should be examined because of
possible selection of typed, compatible donors for transfusion.
4. The presence of alloantibodies should be ruled out.
Recommendations 4.4.5
Warm types of Auto-Immune Haemolytic Anaemia (AIHA)
1.
Prednisone is recommended as the therapy of choice for the classic warm type
auto-immune haemolytic anaemia (WAIHA).
2.
Splenectomy is effective in patients older than six years of age with classic warm
type auto-immune haemolytic anaemia (WAIHA) that have relapsed or are resistant
to prednisone. Splenectomy is only indicated in patients older than six years of age
because of the risk of infection.
3.
Rituximab can be considered in prednisone-resistant patients.
2.
3.
140
4.
5.
6.
7.
8.
9.
10.
11.
141
For an increasing number of blood groups it is now possible to determine the blood group of
the foetus in the mothers plasma and this is the case of the clinically relevant Rhesus and K
antigens. The clinical condition of the foetus can be monitored using echo Doppler of the
flow speed in the Mid Cerebral Artery as a measure of anaemia, if necessary in combination
with amniocentesis to estimate the extent of haemolysis or a cord blood puncture to
measure foetal Hb. Severe haemolysis with hydrops is often (> 80%) the result of RhD
antibodies. Treatment with 2 4 weekly intra-uterine transfusions (IUT) is possible from
week 18 22 for the prevention of hydrops. Large cohort studies have shown that this
treatment is effective and more than 90% of these children are born alive (Van Kamp 2004).
Blood group antagonism, which results in severe anaemia before the 22nd week as is a
possibility with K antagonism has a poorer prognosis (Vaughan 1998, Weiner 1996).
In the Netherlands, treatment with IUT is centralised in the Leiden University Medical Centre
(LUMC), as the occurrence of complications from the procedure is strongly associated with
experience (Van Kamp 2004).
As a result of foeto-maternal transfusion during IUT, the mother has an increased (10
25%) chance of developing additional irregular antibodies (Vietor 1994, Schonewille 2007).
The compatibility study is therefore only valid for 24 hours in these women (Van Kamp 1999,
Health Council 1992). IUT suppresses the production of erythrocytes in the foetus. As a
result, the foetus has primarily erythrocyte antigens from the donor at birth.
Conclusions 4.4.6.1
Blood group antagonism in pregnancy should be detected and if this is
checked according to a protocol it can prevent severe foetal hydrops.
Level 3
C
Level 3
Level 3
Other considerations
Foetal hydrops often has causes other than blood group antagonism (including alpha
thalassaemia and Parvo B19 infection).
142
Recommendations 4.4.6.1
1.
2.
3.
The detection and monitoring of irregular antibodies during pregnancy should occur
according to a protocol.
Severe blood group antagonism resulting in hydrops is an absolute indication for
intra-uterine transfusions (IUT); in order to limit complications, foetal transfusions
should be performed in a centre with maximum experience.
Women undergoing intra-uterine transfusions have a strongly increased risk of blood
group immunisation. It is recommended to perform the compatibility after prior intrauterine transfusions (IUT) with a sample that is as fresh as possible (< 24 hours old).
143
Blood for exchange transfusions for premature babies < 32 weeks or < 1,500 grams should
be irradiated (25 Gy).
In addition to phototherapy and exchange therapy, the intravenous administration of
immunoglobulins (IVIG) is also used. However, the value of this intervention (IV-Ig) is the
subject of discussion. Therefore, the literature was searched using systematic reviews to
examine the effect of IVIG on haemolytic disease of the neonate. The quality of the reviews
was evaluated based on the following items : search strategy, selection of articles, quality
evaluation and analysis method.
Two good systematic reviews were found, including a Cochrane review. Gottstein et al
performed a systematic review and meta-analysis of RCTs on the effect of IVIG on
haemolytic disease of the neonate (Gottstein 2003). Compared to phototherapy alone, IVIG
significantly reduced the number of required exchange transfusions, but the number of
erythrocyte transfusions required for anaemia occurring at a later stage turned out to be
higher in IVIG treated patients (Gottstein 2003). Alcock et al drew similar conclusions in their
Cochrane review (Alcock 2002). However, they emphasised that the conclusions were
based on only 3 trials with a total of 189 patients. In addition, only 1 trial met the criteria for
high quality. Absence of randomly assigned treatment was a significant shortcoming in the
other trials. None of the trials used a placebo and there was also no blinding. The Cochrane
reviewers concluded that due to these limitations the value of IVIG is uncertain and that
this treatment cannot be recommended as a routine treatment, also due to the absence of
information about the long-term safety (Alcock 2002).
A recent double-blind, placebo-controlled, randomised study of the efficacy of IVIG in
haemolytic disease of the neonate found no difference between the IVIG and placebo
groups (Smits-Wintjens, Pediatrics 2011, in press).
Conclusions 4.4.6.2
Level 3
Level 4
Level 3
144
Expert opinion
Level 3
Smits-Wintjens 2008
Gottstein 2003
Alcock 2002
Smits- Wintjens 2011
Rhesus
disease
Alcock,
Neonates
Cochrane
Good;
High dose Photothe
2002
with
iso- review
included
IVIG +
rapy
immune
RCTs
photothera alone
haemolytic
moderate
py
disease
SmitsWintjens,
2011
Neonates
with
isoimmune
haemolytic
disease
Doubleblind,
placebocontrolled
RCT
Good
High dose
IVIG +
photothera
py
Placebo
+
photothe
rapy
Outcome
Result
I vs C
Comments
# children RR 0.28; CI
with
0.17 0.47
exchange
transfusion
s
RR 0.21; CI
0.10 0.45
Use
of RR 0.28;
exchange
0.17 0.47
transfusion
s
CI Only
3
moderate
RCTs with
a total of
189
patients
Ordinary
RR 11; CI 0.62 Triggers for
transfusion 195
transfusion
s after the
varied
st
1 week
Duration of WMD 22; CI Long-term
photothera 35,-9.9
safety
py
unknown
# children No difference in
with
exchange
exchange
transfusions
transfusion between both
s
groups
Duration of No difference in
photothera phototherapy
py,
days or bilirubin
maximum
level between
bilirubin
both groups
level
145
Recommendations 4.4.6.2
1.
2.
3.
4.
4.5
The normal Hb level for neonates born full-term is 12 mmol/L (SD: 1.4), of which 60 80% is
HbF. The switch to adult Hb starts in the 32 nd week after conception. In premature neonates,
the normal Hb at birth is lower and this decreases in a linear fashion proportional to the
duration of the pregnancy (Jopling 2009, Nicolaides 1989). The Hb concentration decreases
after birth due to:
an increase in 2,3 diphosphoglycerate (2,3-DPG);
a shortened life span of HbF containing red cells;
rapid expansion of the blood volume;
decrease in the epoietin level (due to increase in arterial pO 2);
blood sample collections;
clamping the umbilical cord too soon.
In a full-term neonate, the Hb drops to a physiological level of 6.8 mmol/L (SD: 1.2) after
approximately 8 weeks. Transfusions are almost never indicated, nor is the routine
administration of iron effective (Franz 2000, Irigoyen 1991, Heese 1990). In premature
babies < 1,500 grams, the Hb concentration can decrease from 10 to 5 mmol/L after 4 8
weeks, partially due to blood sample collection for diagnostic tests. Enteral iron
administration (in the form of ferrous fumarate, 6 mg/kg/day in 3 doses) is useful for
premature babies as soon as complete enteral feeding is possible and this reduces the need
for transfusions after the second week of life (Franz 2000). Intramuscular iron has no
benefits over oral iron supplementation (Heese 1990). Most transfusions are given to very
low birth weights (VLBW) children after a pregnancy of 24 to 32 weeks; this involves 1
1.5% of all births, in other words 2,000 3,000 per year in the Netherlands. A lot of research
has been performed on the administration of epoietin to premature infants (Aher 2006,
Ohlsson 2006). The reduction of the quantity of allogeneic erythrocytes administered was
usually the primary measure of outcome. Two Cochrane meta-analyses showed that the
clinical significance of both early and late administration of epoietin is very limited (Aher
2006, Ohlsson 2006, Aher 2006). Particularly with late administration of epoietin there is an
average reduction of the transfusion volume of 7 mL/kg (< 1 neonatal unit EC) (Aher 2006).
Both Cochrane reviews concluded that there is insufficient proof to recommend epoietin
146
administration for neonatal anaemia (Aher 2006, Ohlsson 2006, Aher 2006). Epoietin
administration can be considered in special cases, such as Jehovahs Witnesses.
There are two important strategies for reducing anaemia in the (premature) neonate and
thereby reducing the number of blood transfusions, namely:
1.
late clamping of the umbilical cord at birth;
2.
limiting the number of blood sample collections.
Ad 1. Various meta-analyses have shown that late clamping of the umbilical cord (at least 30
seconds to a maximum of 2 or 3 minutes after birth) is important in reducing anaemia, both
in premature (Rabe 2008, 2004) and full-term neonates (Hutton 2007). In addition to
reducing anaemia and the need for blood transfusions, late clamping also results in a
decrease in intracranial haemorrhages (RR: 1.74; 95% - CI 1.08 2.81) (Rabe 2004) without
an increase in polycythaemia or hyperbilirubinaemia that would require treatment (Ultee
2008, Mercer 2006, Ceriani Cernadas 2006).
Ad 2. Blood loss in premature infants due to blood sample collections varies from 1.1 to 3.5
mL/kg/day (Alagappan 1998, Obladen 1988, Nexo 1981, Kakaiya 1979). Micro methods for
laboratory blood analysis are important in reducing blood loss due to blood sample
collections (Widness 2005, Lin 2000, Ringer 1998). Reduction of blood loss results in a
reduction in the number of blood transfusions (Madan 2005).
147
these studies can be found in the evidence table. The study by Bell et al (Bell 2005) was
downgraded as the reporting appeared to have been extremely selective. Ultimately, an
effect was only found for a liberal transfusion policy with an unusual measure of outcome.
The better RCT by Kirpalani et al (Kirpalani 2006) (the so-called PINT study; Premature
Infants in Need of Transfusion)
found no difference between an algorithm with a low Hb trigger an
d a high Hb trigger for various clinically relevant measures of outcome. In the group with a
low Hb trigger, fewer children required one or more blood transfusions than in the group with
a high Hb trigger, 89% versus 95% respectively, p = 0.04. Although no significant difference
was found between both groups in relation to the long-term psychomotor development, a
post-hoc analysis showed a better mental development in the group with a higher Hb trigger
(Whyte 2009).
Due to the scarcity of good studies, it is not possible to make reliable recommendations
concerning optimal transfusion triggers in neonates. Further study (with follow-up) of a more
restrictive transfusion policy in premature neonates is essential.
Commonly used transfusion triggers in the Dutch NICUs (not based on research) are:
Maintaining Hb = 8 mmol/L with ventilation, whilst avoiding an Ht > 0.50 L/L (Strauss
1995, Brown 1990).
Maintaining an Hb > 7 mmol/L in stable neonates with cardiopulmonary abnormalities
and use of oxygen (Strauss 1995, Brown 1990).
Maintaining Hb > 6 mmol/L in stable premature infants < 4 weeks, particularly in the
first four weeks of life when anaemia and tissue hypoxia can lead to apnoea.
Maintaining Hb > 4.5 mmol/L in stable premature infants > 4 weeks (Strauss 1995,
Brown 1990).
148
Kirpalani
Bell
25
Brooks
Ross
29
28
26
year
Study
design
level
Quality
aspects*
Study
population
Intervention
outcome
2006
RCT
A2
S, A, C, R:
OK
B: Blinding
outcome
assessors
only partly
Premature
neonates <
31 wks;
<1000 g
451
Algorithm of
low vs. high
Hb trigger
(restrictive
vs. liberal
transfusion
policy)
No difference in blood
transfusions;
OR composite
outcome (mortality,
severe
bronchopulmonary
dysplasia, retinopathy
of prematurity or
cerebral damage 1.30
(0.83, 2.02)
2005
RCT
S, A, B, C:
OK
R:
Selective
reporting!
Premature
neonates;
500-1300 g
100
Algorithm of
low vs. high
Hb trigger
(restrictive
vs. liberal
transfusion
policy)
No difference in blood
transfusions;
Fewer cases of grade
IV intraventricular
haemorrhage or
periventricular
leukomalasia 0% vs
12% (p=0.012)
1999
RCT
Risk of
bias
cannot be
assessed
Premature
neonates <
1251 g
50
Ht 0.20
0.30 L/L+
specific
medical
criteria vs. Ht
>=0.40
No difference in
retinopathy: 83%; vs.
73%; CI 52%, 88%.
(p=0.38).
1989
RCT
(B)
Risk of
bias
cannot be
assessed
Premature
neonates <
32 weeks
16
Transfusion
to Ht of 0.40
L/L vs no
transfusion
for 3 days
No differences
Other
considerations
Artificial combined
neurological
measure of
outcome
only thought of
post-hoc. Many
methodological
queries
concerning
interpretation of
the secondary
measures of
outcome.
Small study;
duration of study
only 3 days: not
relevant
149
solution is not a problem even at the end of the storage duration (35 days), despite the high
potassium concentration (> 50 mmol/L). In order to reduce the number of donor expositions,
an erythrocyte concentrate from one donor can be split into a number of so called pedipacks (usually 4 pedipacks of 50 ml) (Widness 1996, Andriessen 1993, Patten 1991). A
premature infant receives an average of two (range: 0-10) pedi-packs. Please see Chapter
3.3.3.2, compatibility study for further details concerning the compatibility study for blood
transfusions.
During the initial care of a neonate with very severe anaemia due to acute bleeding, it is
possible to increase the immediate post-partum Hb without causing volume overload by
means of a partial exchange transfusion using uncrossed O-RhD negative erythrocytes
Conclusions 4.5
Level 1
Level 1
A2
B
C
Widness 2005
Madan 2005
Lin 2000
Kirpalani 2006
Bell 2005, Whyte 2009, Brooks 1999
Recommendations 4.5
1.
2.
150
Clamping the umbilical cord of premature and full-term neonates should only take
place after at least 30 seconds and no more than 2 3 minutes after birth.
Iatrogenic blood loss due to blood sample collections in premature neonates should
be reduced by using among others micro-analysis techniques and by limiting the
number of blood tests.
3.
4.
5.
6.
7.
8.
4.6
Approximately 3.5 4.2% of all erythrocyte transfusions are given to children, defined here
as patients younger than 18 20 years (Cobain 2007, Stainsby 2008). In 69% of the children
receiving a transfusion, the number of transfusions remains limited to one (Slonim 2008). A
complication as a result of a transfusion occurs in less than 1% of these patients (Slonim
2008). An English report was published recently about severe side effects of blood
transfusion, specifically in children (Stainsby 2008). The incidence of severe side effects is
estimated in this report at 18:100,000 transfusions for children aged 1 18 years and double
that for children < 1 year. Examples of severe side effects are (in order of decreasing
frequency): incorrect blood component administered, acute or delayed transfusion reaction,
TRALI, graft versus host disease and transmission of infection. Children over the age of four
months primarily receive erythrocyte transfusions in the ICU, peri-operatively, due to blood
loss after trauma, because of (treatment of) cancer, sickle cell disease, thalassaemia or a
primary bone marrow condition associated with (among others) insufficient red cell
production. Erythrocyte transfusions for neonates are discussed in paragraph 4.5,
erythrocyte transfusions in acute situations are discussed in Chapter 5.
There are few if any studies that compared various erythrocyte transfusion triggers for
children over the age of four months. As a result, guidelines for this category of children are
based largely on empirical evidence or have been extrapolated from studies in adults. The
best and most recent guideline concerning erythrocyte transfusions for neonates and older
children is from the United Kingdom (Gibson 2004). Usually, erythrocyte transfusions are
given at Hb values between 4.0 and 5.0 mmol/L; the indication is partly determined by the
symptoms (Wong 2005, Gibson 2004, Slonim 2008).
4.7
Specific Diseases
151
Viele MK, Weiskopf RB. What can we learn about the need for transfusion from patients who
refuse blood? The experience with Jehovas Witness. Transfusion 1994;34:396-401.
Weiskopf RB, Viele MK, Feiner J, Kelly S, Lieberman J, Noorani M, et al. Human
cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA
1998;279:217-21.
Literature 4.2.1
1.
2.
3.
4.
5.
6.
Andrews CM, Lane DW, Bradley JG. Iron-preload for major joint replacement. Transfus Med
1997;7:281-6.
Fotland SS. Transfus. Aspher. Sci.2009 april 17 (ePub ahead of print )
Liddler, PG. Ann R Coll Surg Engl 2007;89(4):418-21.
Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency
in the United States. JAMA 1997;277:973-6.
Mundy GM. J Bone Joint Surg Br 2005;87(2):213-7.
Munoz M. Med Clin (Barc) 2009;132(8):303-6
Literature 4.2.2
1.
2.
3.
4.
Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response
in patients with anemia of cancer. N Engl J Med 1990;322:1689-92.
Skillings JR, Rogers-Melamed I, Nabholtz JM, Sawka C, Gwadry-Sridhar F, Moquin JP, et al.
The frequency of red cell transfusions for anemia in patients receiving chemotherapy. Cancer
Prev Control 1999;3:207-12.
Skillings JR, Sridhar FG, Wong C, Paddock L. The frequency of red cell transfusion for
anemia in patients receiving chemotherapy. A retrospective cohort study. Am J Clin Oncol
1993;16:22-5.
Wood PA, Hrushesky WJ. Cisplatin-associated anemia: an erythropoietin deficiency
syndrome. J Clin Invest 1995;95:1650-9.
Literature 4.2.2
1.
2.
Fluit CR, Kunst VA, Drenthe-Schonk AM. Incidence of red blood cell antibodies after multiple
transfusions. Transfusion 1990;30:532-5.
Schonewille H, Haak HL, Zijl AM van. Alloimmunization after blood transfusions in patients
with hematologic and oncologic diseases. Transfusion 1999;39:763-71.
Literature 4.2.2
1.
Literature 4.2.3
152
1.
2.
3.
4.
5.
6.
7.
Consensus development panel: morbidity and mortality of renal dialysis: an NIH consensus
conference statement. Ann Int Med 1994;121:62-70.
Delano BG. Improvements in quality of life following treatment with rHuEPO in anemic
hemodialysis patients. Am J Kidney Dis 1989;14(2 Suppl 1):14-8.
Evans RW, Rader B, Manninen DL. The quality of life of hemodialysis recipients treated with
recombinant human erythropoietin. The Cooperative multicenter EPO Trial. JAMA
1990;263:825-30.
NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure.
National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis 1997;30(4
Suppl 3):S192-240.
Mocks J. Analysis of safety database for long term epoetin-beta treatment. Meta analysis
covering 3697 patients. In: Koch KM, unter Stein G (eds). Pathogenic and therapeutic aspects
of chronic renal failure. New York: Becker Medical Library Books, 1997. p. 163-97.
Sokol L, Prchal T. Pure red cell aplasia and recombinant erythropoietin. N Engl J Med
2002;346:1584-6.
NIH consensus 1994.
Literature 4.2.4
1.
2.
3.
4.
Literature 4.2.5
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
153
12.
13.
Literature 4.2.6
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
154
Benjamin RJ, Antin JH. ABO-incompatible bone marrow transplantation: the transfusion of
incompatible plasma may exacerbate regimen-related toxicity. Transfusion 1999;39:1273-4.
Bolan CD, Childs RW, Proctor JL, Barrett AJ, Leitman SF. Massive immune hemolysis after
allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility. Br J
Haematol 2001;112:787-95.
Bornhauser M, Ordemann R, Pauz U, Schuler U, Kompf J, Holig K, et al. Rapid engraftment
after ABO-incompatible peripheral blood progenitor cell transplantation complicated by severe
hemolysis Bone Marrow Transplant 1997;19:295-7.
Chan KW, Unrau L, Denegri JF. ABO incompatible marrow transplant. Transfusion
1983;23:80-1.
Chen FE, Owen I, Savage D, Roberts I, Apperley J, Goldman JM, et al. Late onset
haemolysis and red cell autoimmunisation after allogeneic bone marrow transplant. Bone
Marrow Transplant 1997;19:491-5.
Drobyski WR, Potluri J, Sauer D, Gottschall JL. Autoimmune hemolytic anemia following T
cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant
1996;17:1093-9.
Fitzgerald JM, Conn JS, Proctor SJ. Severe hemolysis complicating the rapid engraftment of
a minor ABO mismatched peripheral blood stem cell allogenic transplant [Abstract]. Int Symp
Autologous PBSCT; 1999 ; Mulhouse, France.
Gajewski JL, Petz LD, Calhoun L, ORourke S, Landaw EM, Lyddane NR, et al. Hemolysis of
transfused group O red blood cells in minor ABO-incompatible unrelated-donor bone marrow
transplants in patients receiving cyclosporine without posttransplant methotrexate. Blood
1992;79:3076-85.
Godder K, Pati AR, Abhyankar SH, Lamb LS, Armstrong W, Henslee-Downey PJ. De novo
chronic graft-versus-host disease presenting as hemolytic anemia following partially
mismatched related donor bone marrow transplant. Bone Marrow Transplant 1997;19:813-7.
Greeno EW, Perry EH, Ilstrup SJ, Weisdorf DJ. Exchange transfusion the hard way: massive
hemolysis following transplantation of bone marrow with minor ABO incompatibility.
Transfusion 1996;36:71-4.
Heal JM, Blumberg N. The second century of ABO: and now for something completely
different. Transfusion 1999;39:1155-9.
Hershko C, Gale RP, Ho W, Fitchen J. ABH antigens and bone marrow transplantation. Br J
Haematol 1980;44:65-73.
Horn B, Viele M, Mentzer W, Mogck N, DeSantes K, Cowan M. Autoimmune hemolytic
anemia in patients with SCID after T cell-depleted BM and PBSC transplantation. Bone
Marrow Transplant 1999;24:1009-13.
Hows J, Beddow K, Gordon-Smith E, Branch DR, Spruce Sniecinski I. Donor-derived red
blood cell antibodies in immune hemolysis after bone marrow transplantation. Blood
1996;67:177-81.
Hows J, Beddow K, Gordon-Smith E, Branch DR, Spruce W, Sniecinski I, et al. Donor derived
red blood cell antibodies and immune hemolysis after allogeneic bone marrow
transplantation. Blood 1986;67:177-81.
Hows J, Beddow K, Gordon-Smith E, Branch DR, Spruce W, Sniecinski I, et al. Donor-derived
red blood cell antibodies and immune hemolysis after allogeneic bone marrow
transplantation. Blood 1997;67:177-81
Klumpp TR. Complications of peripheral blood stem cell transplantation. Semin Oncol
1995;22:263-70.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Literature 4.2.7
1.
Literature 4.3.1
1.
Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, et al.
2.
Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev 2004; 3:
CD003407.
Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, et al. Erythropoietin
or darbepoietin for patients with cancer. Cochrane Database Syst Rev 2006; 3: CD003407.
155
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, sterborg A, et al. EORTC guidelines
for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J
Cancer 2007; 43: 258-270.
Jones M, Schenkel B, Just J, Fallowfield L. Epoetin alfa improves quality of life in patients
with cancer: results of metaanalysis. Cancer 2004; 101: 1720-1732.
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B, Epoetin Alfa Study Group.
Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients
receiving nonplatina chemotherapy: results of a randomized, double-blind, placebo-controlled
trial. J Clin Oncol 2001;19:2865-74.
Littlewood TJ, Nortier J, Rapoport B, Pawlicki M, de Wasch G, Vercammen E, Schuette W,
Wils J, Freund M; Epoetin Alfa Study Group. Epoetin alfa corrects anemia and improves
quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy.
Hematol Oncol. 2003 Dec;21(4):169-80.
Marec-Berard P, Chastagner P, Kassab-Chahmi D, Casadevall N, Marchal C, Misset JL, RayCoquard I. 2007 Standards, Options, and Recommendations: use of erythropoiesisstimulating agents (ESA: epoetin alfa, epoetin beta, and darbepoetin) for the management of
anemia in children with cancer. Pediatr Blood Cancer. 2009 Jul;53(1):7-12.
Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response
in patients with anemia of cancer. N Engl J Med 1990;322:1689-92.
Oberhoff C, Neri B, Amadori D, Petry KU, Gamucci T, Rebmann U, et al. Recombinant
human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of
transfusion requirement associated with solid tumors: a randomized, controlled study. Ann
Oncol 1998; 9 (3):239-41.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in
health-related quality-of-life scores. J Clin Oncol 1998; 16: 139-144.
Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in
patients with cancer: evidence-based clinical practice guidelines of the American Society of
Clinical Oncology and the American Society of Hematology. Blood 2002;100:2303-20.
Literature 4.3.2
1.
2.
Literature 4.3.3
1.
2.
3.
4.
5.
156
Thompson JA, Gilliland DG, Prchal JT, Bennett JM, Larholt K, Nelson RA, Dugan MH. Effect
of recombinant human erythopoietin combined with granulocyte/macrophage colonystimulating factor in the treatment of patients with myelodysplastic syndromes. Blood
2000;95:1175-9.
Aloe Spiriti MA, Petti MC, Latagliata R, Avvisati G, Gregoris C de, Proia S, et al. Is
recombinant human erythropoietin treatment in myelodysplasia syndromes worthwhile? Leuk
Lymphoma 1993;9:79-83.
Cazzola M, Ponchio L, Beguin Y, Rosti V, Bergamaschi G, Liberato NL, et al. Subcutaneous
erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase
I/II clinical trial. Blood 1992;79:29-37.
Cazzola M, Ponchio L, Pedrotti C, Farina G, Cerani P, Lucotti C, Novella A, Rovati A,
Bergamaschi G, Beguin Y. Prediction of response to recombinant human erythropoietin
(rHuEpo) in anemia of malignancy. Haematologica. 1996;81:434-41.
Goy A, Belanger C, Casadevall N, Picard F, Guesnu M, Jaulmes D, et al. High dosis of
intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic
syndrome. Br J Haematol 1993;84:232-7.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Hellstrom-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a metaanalysis of 205 patients from 17 studies. Br J Haematol 1995;89:67-71.
Iki S, Yagisawa M, Ohbayashi Y, Sato H, Urabe A. Adverse effect of erythropoietin in
myeloproloferative disorders. Lancet 1991;337:187-8.
Isnard F, Najman A, Jaar B, Fenoux P, Naillou C. Efficacy of human recombinant
erythropoietin in the treatment of refractory anaemia with excess blast in myelodysplastic
syndrome. Leuk Lymph 1994;12:307-14.
Italian MDS study group. A randomized double-blind placebo-controlled study with
subcutaneous recombinant human erythropoietin in patients with low risk myelodysplastic
syndromes. Br J Haematol 1998;103:1070-4.
Jones D, Zeigler ZR, Rosenfeld CS, Shadduck RK. Unmaintained trilineage respons to
recombinant human erythropoietin in a patint with myelodysplasia. Br J Haematol
1992;80:406-7.
Ludwig H, Fritz E, Leitgeb C, Krainer I. Erythropoietin treatment for chronic anemia of
selected haematological patients. Ann Oncol 1993;4:161-7.
Motoji T, Hoshino S, Ueda M, Takanashi M, Masuda M, Nakayama K, et al. Enhanced growth
of clonogenic cells from acute myeloblastic leukaemia by erythropoietin. Br J Haematol
1990;75:60-7.
Musto P, Scalzulli PR, Carotenuto M. Recombinant erythropoietin for myelodysplastic
syndromes. Br J Haematol 1995;91:235-58.
Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in
patients with cancer: evidence-based clinical practice guidelines of the American Society of
Clinical Oncology and the American Society of Hematology. Blood 2002;100:2303-20.
Rose EH, Abels RI, Nelson RA, McCullough DM, Lessin L. The use of r-HuEpo in the
treatment of anaemia related to myelodysplasia (MDS). Br J Haematol 1995;89:831-7.
Shapiro S, Gershon H, Rosenbaum H, Merchan S. Characterization of circulating
erythrocytes from myelodysplastic patients treated with recombinant human erythropoietin.
Leukaemia 1993;9:1328-33.
Stenke L, Wallvik J, Celsing F, Hast R. Prediction of response to treatment with human
recombinant erythropoietin in myelodysplasyic syndromes. Leukemia 1993;7:1324-7.
Zeigler ZR, Jones D, Rosenfeld CS, Shadduck RK. Recombinant human erythropoietin
(rHuEPO) for treatment of myelodysplastic syndrome. Stem Cells 1993;11:49-55.
Sokol L, Prchal T. Pure red cell aplasia and recombinant erythropoietin. N Engl J Med
2002;346:1584-6.
Literature 4.3.4
1.
2.
3.
4.
5.
6.
Delano BG. Improvements in quality of life following treatment with rHuEPO in anemic
hemodialysis patients. Am J Kidney Dis 1989;14(2 Suppl 1):14-8.
European best practice guidelines for the management of anemia in patients with chronic
renal failure. Nephrol Dial Transplant 1999;14(Suppl 5).
Evans RW, Rader B, Manninen DL. The quality of life of hemodialysis recipients treated with
recombinant human erythropoietin. The Cooperative multicenter EPO Trial. JAMA
1990;263:825-30.
NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure.
National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis 1997;30(4
Suppl 3):S192-240.
KDOQI clinical practice guidelines and clinical practice recommendations for anemia in
chronic kidney disease. Am J Kidney Dis 2006; 47(5 Suppl 3): S1618.
KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic
kidney disease, 2007 update of hemoglobin target. Am J Kidney Dis 2007; 50(3): 471530.
Literature 4.3.5
157
1.
2.
3.
4.
5.
6.
7.
8.
Gasche C, Dejaco C, Walehoer T, Tillinger W, Reinisch W, Fueger CF, et al. Intravenous iron
and erythropoietin for anemia associated with Crohns disease. Double blind placebocontrolled trial. Ann Int Med 1997;126:782-7.
Henry DH Experience with epoietin alfa and acquired immunodeficiency syndrome. Semin
Oncol 1998;25(3 Suppl 7):64-8.
Kreuzer KA, Rockstroh JK, Jelkmann W, Theisen A, Spengler U, Sauerbruch T. Inadequate
erythropoietin response to anemia in HIV patients: relationships to serum levels of TNF-alpha,
IL-6 and their soluble receptors. Br J Haematol 1997;96:235-9.
Murphy EA.Study of erythropoietin in treatment of anemia in patients with rheumatoid arthritis.
BMJ 1994;309:1337-8.
Nordstrm D, Lindroth Y, Marsal L, Hafstrom I, Henrich C, Rantapaa-Dahlqvist S. Availability
of iron and degree of inflammation modifies the response to recombinant human
erythropoietin when treating anemia of chronic disease in patients with rheumatoid arthritis.
Rheumatol Int 1997;17:67-73.
Peeters HR, Jongen-Lavrencic M, Bakker CH, Vreugdenhil G, Breedveld FC, Swaak AJ.
Recombinant human erythropoietin improves health-related quality of life in patients with
rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with
disease activity measures. Rheumatol Int 1999;18:201-6.
Peeters HR, Jongen-Lavrencic M, Vreugdenhil G, Swaak AJ. Effect of recombinant human
erythropoietin on anemia and disease activity in patients with rheumatoid arthritis and anemia
of chronic disease: a randomized placebocontrolled double blind 52 weeks clinical trial. Ann
Rheum Dis 1996;55:739-44.
Schreiber S, Howaldt S, Schnoor M, Nikolaus S, Banditz J, Gasche C, et al. Recombinant
erythropoietin for the treatment of anemia in inflammatory bowel disease. N Engl J Med
1996;334:619-23.
Literature 4.3.6
1.
2.
3.
Literature 4.4.1
1.
2.
3.
4.
5.
6.
158
Adams RJ, Brambilla D. The Optimizing Primary Stroke Prevention in Sickle Cell Anemia
(STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in
sickle cell disease. N Engl J Med 2005; 353: 2769 2778.
Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with
sickle cell anemia and abnormal results on transcranial doppler ultrasonography. N Engl J
Med 1998; 339: 5 11.
Alexy T, Pais E, Armstrong JK, et al. Rheologic behavior of sickle and normal red blood cell
mixtures in sickle plasma: implications for transfusion therapy. Transfusion. 2006 Jun;46:9128.
Alhashimi D, Fedorowicz Z, Alhashimi F, et al. Blood transfusions for treating acute chest
syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2010 Jan 20;(1).
Alstiza JM, Artetxe J, Castiella A, et al. MR quantification of hepatic iron concentration.
Radiology. 2004; 230:479-84.
Armstrong FD, Thompson RJ Jr, Wang W, et al. Cognitive functioning and brain magnetic
resonance imaging in children with sickle Cell disease. Neuropsychology Committee of the
Cooperative Study of Sickle Cell Disease. Pediatrics 1996; 97:864-70.
Blood Transfusion Guideline, 2011
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Charache S, Lubin B, Reid CD, et al. Management and therapy of sickle cell disease. No. 922117. Washington, DC: US department of Health and Human Service, National Institutes of
Health Publication, 1992. p. 20.
Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful
crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle
Cell Anemia. N Engl J Med. 1995; 332:1317-22.
Cohen AR, Martin MB, Silber JH, et al. A modified transfusion program for prevention of
stroke in sickle cell disease. Blood 1992;79:1657-61.
Emre U, Miller ST, Gutierez M, et al. Effect of transfusion in acute chest syndrome of sickle
cell disease. J Pediatr 1995;127:901-4.
Hankins J. Chronic transfusion therapy for children with SCD and recurrent acute chest
syndrome. J Pediatr Hematol Oncol 2005; 27:258-61.
Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially
catastrophic complication of severe sickle cell pain episodes. Am J Med. 1994; 96:155-62.
Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with
simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a
retrospective cohort study of 137 children with sickle cell anemia. J Pediatr 2006; 149:710-2.
Josephson CD, Su LL, Hillyer KL et al. Transfusion in the patient with sickle cell disease: a
critical review of the literature and transfusion guidelines. Transfus Med Rev. 2007; 21:11833.
Kirk P, Roughton M, Porter JB, et al. Cardiac T2* magnetic resonance for prediction of
cardiac complications in thalassemia major. Circulation. 2009; 120:1961-8.
Koshy M, Burd L, Wallace D, et al. Prophylactic red-cell transfusions in pregnant females with
sickle cell disease. A randomized cooperative study. N Eng. J Med 1988; 319: 1447-52.
Koshy M, Weiner SJ, Miller ST, et al Surgery and anesthesia in sickle cell disease.
Cooperative Study of Sickle Cell Diseases. Blood 1995; 86:3676-84.
Mallouh AA, Asha M. Beneficial effect of blood transfusion in children with sickle cell chest
syndrome. Am J Dis Child. 1988;142:178-82.
Manci EA, Culberson DE, Yang YM, et al. Causes of death in sickle cell disease: an autopsy
study. Br J Haematol 2003; 123: 359 65.
Merritt AL ,Haiman C,Henderson SO, et al. Myth: blood transfusion is effective for sickle cell
anemia-associated priapism.Canadian Journal of Emergency Medical Care 2006; 8:119-122
Miller ST, Wright E, Abboud M, et al. Impact of chronic transfusion on the incidence of pain
and ACS during the Stroke Prevention Trial (STOP) in sickle cell anemia. J Pediatr 2001;
139:785-9.
Neumayr L, Koshy M, Haberkern C, et al. Surgery in patients with hemoglobin SC disease.
Preoperative Transfusion in Sickle Cell Disease Study Group. Am J Hematol. 1998; 57:101-8.
Ohene-Frempong K. Stroke in sickle cell disease: demographic, clinical, and therapeutic
considerations. Semin Hematol 1991;28:213-9.
Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell
disease: rates and risk factors. Blood 1998; 91:288-94.
Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol
2001;38(1 Suppl 1):5-13.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk
factors. N Engl J Med. 1991; 325:11-6.
Powers DR. Management of cerebral vasculopathy in children with sickle cell anaemia. Br J
Haematol. 2000;108:666-78
Rana S, Houston PE, Surana N, et al. Discontinuation of long-term transfusion therapy in
patients with sickle cell disease and stroke. J Pediatr 1997;131:757-60.
Rosse WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmunization in sickle cell
disease. The Cooperative Study of Sickle Cell Disease. Blood 1990; 76:1431-7.
Russell MO, Goldberg HI, Hodson A, et al. Effect of transfusion therapy on arteriographic
abnormalities and on recurrence of stroke in sickle cell disease. Blood 1984;63:162-9.
Russell MO, Goldberg HI, Reis L, et al. Transfusion therapy for cerebrovascular abnormalities
in sickle cell disease. J Pediatr 1976;88:382-7.
159
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
Sarnaik S, Soorya D, Kim J, et al. Periodic transfusions for sickle cell anemia and CNS
infarction. Am J Dis Childhood 1979;133:1254-7.
Smith-Whitley K, Zhao H,. Hodinka RL. Epidemiology of human parvovirus B19 in children
with sickle cell disease. Blood 2004;422-427.
Styles LA, Abboud M, Larkin S, et al. Transfusion prevents acute chest syndrome predicted
by elevated secretory phospholipase A2. Br J Haematol 2006; 136: 343 44.
Turner JM, Kaplan JB, Cohen HW, et al. Exchange versus simple transfusion for acute chest
syndrome in sickle cell anemia in adults. Transfusion 2009; 49:863-68.
Vichinsky EP, Earles A, Johnson RA, et al. Alloimmunization in sickle cell anemia and
transfusion of racially unmatched blood. N Engl J Med 1990;322:1617-21.
Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive
transfusion regimens in the perioperative management of sickle cell disease 1995; 333: 206
13.
Vichinsky EP, Luban NL, Wright E, et al. Prospective RBC phenotype matching in a strokeprevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion
2001;41:1086-92.
Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of deferasirox versus
deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J
Haematol. 2007;136:501-8.
Wahl S, Quirolo KC. Current issues in blood transfusion for sickle cell disease. Curr Opin
Pediatr 2009; 21:15-21.
Wang WC, Kovnar EH, Tonkin IL, et al. High risk of recurrent stroke after discontinuance of
five to twelve years of transfusion therapy in patients with sickle cell disease. J Pediatr
1991;118:337-78
Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin N
Am 2005; 19: 803 26.
Wayne AS, Kevy SV, Nathan DG et al. Transfusion Management of sickle cell disease. Blood
1993;81:1109-23. 2. Davies SC, Olatunji PO. Blood transfusion in sickle cell disease. Vox
Sang 1995;68:145-51.
Wilimas J, Goff JR, Anderson HR Jr, et al. Efficacy of transfusion therapy for one to two years
in patients with sickle cell disease and cerebrovascular accidents. J Pediatr 1980;96:205-8.
Literature 4.4.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
160
Literature 4.4.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Brecher ME, Taswell HF. Paroxysmal noctural hemoglobinuria and the transfusion of washed
cells. Transfusion 1998;29:681-85.
Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal
nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. 2000;114:459-466.
Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement
inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria.
Blood. 2008; 111:1840-1847.
Fitzgerald JM, McCann SR, Lawlor E. Transfusion in paroxysmal noctural haemoglobinuria: a
change of policy. Transfus Med 1994;4:246.
Henry JB. Clinical diagnosis and management by laboratory methods. 17th ed. Philalelphia:
Saunders, 1984.
Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion
requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med.
2004;350:552-559.
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal
nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-1258
Hillmen P, Muus P, Duhrsen U, et al. Effect of thecomplement inhibitor eculizumab on
thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood.
2007;110:4123-4128.
Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal
nocturnal hemoglobinuria. N Engl J Med. 2006; 355:1233-1243.
Sirchia G, Zanell A. Transfusion of PNH patients. Transfusion 1990;30:479.
Literature 4.4.4
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
161
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
162
Kamp IL van, Klumper FJMC, Meerman RH, Brand A, Bennebroek Gravenhorst J, Kanhai
HHH. Bloedgroepimmunisatie: resultaten van behandeling van foetale anemie met
intrauteriene intravasculaire bloedtransfusie in Nederland, 1987-1995. Ned Tijdschr
Geneeskd 1999;143:2527-31.
Koelewijn JM, Vrijkotte TGM, van de Schoot CE, Bonsel GJ, de Haas M. Effect of screening
for red cell antibodies other than anti-D, to detect haemolytic disease of the fetus and
newborn: a population study in the Netherlands. Transfusion 2008;48:941-52.
Preventie zwangerschapsimmunisatie. Den Haag: Gezondheidsraad, 1992.
Schonewille H,Klumper FJCM, van de Watering LMG, Kanhai HHH, Brand A. High additional
maternal red cell alloimmunization after Rh- and K matched intrauterine intravascular
transfusions for haemolytic disease of the fetus. Am J Obstet Gynecol. 2007;196: 143-6.
Van Kamp IL, Klumper FJCM, Meerman RH, Oepkes D, Scherjon SA, Kanhai HHH.
Treatment of fetal anemia duet o red cell alloimmunization with intrauterine transfusions in the
Netherlands 1988-1999 Acta Obstet Gyn Scand 2004; 83: 731-7.
Van Kamp IL, Klumper FJCM, Oepkes D, Meerman RH, Scherjon SA, Vandebussche FPHA,
Kanhai HHH. Complications of intrauterine transfusion for fetal anemia due to maternal red
cell alloimmunizatiion . Am J Obstet Gyn 2004; 191.
Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts IGA. Inhibition of
erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Med
1998;338:798-803.
Vietor HE, Kanhai HHH, Brand A. Induction of additional red cell alloantibodies after
intrauterine transfusion. Transfusion 1994;34:970.
Weiner CP, Widness JA. Decreased fetal erythropoiesis and hemolysis in Kell hemolytic
anemia. Am J Obstet Gynecol 1996;174:547-51.
Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates.
Cochrane Database Syst Rev. 2002;CD003313.
Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic
disease of the newborn. Arch Dis Child Fetal Neonatal Ed. 2003;88:F6-10.
Blood Transfusion Guideline, 2011
12.
13.
Smits-Wintjens VEHJ, Walther FJ, Lopriore E. Rhesus haemolytic disease of the newborn:
Postnatal management, associated morbidity and long-term outcome. Semin Fetal Neonatal
Med. 2008 Aug;13(4):265-71.
Smits-Wintjens VEHJ, Walther FJ, Oepkes D, Kanhai HHH, Brand A, Lopriore E. Intravenous
immunoglobuline in the treatment of Rhesus disease of the neonate. A randomized double
blind placebo.
Literature 4.4.6.
14.
15.
16.
17.
18.
19.
Luban 1995.
Petaja 2000
Ip 2004,
Jackson 1997
Maisels 1974
Smits-Wintjens VEHJ, Walther FJ; Rath MEA; Lindenburg ITM, te Pas AB, Kramer CM,
Oepkes D, Brand A, Lopriore E. Intravenous immunoglobulin in neonates with Rhesus
hemolytic disease: a randomized double-blind placebo-controlled trial. Pediatrics , accepted
for publication
Literature 4.5
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Jopling J, Henry E, Wiedmeier SE, Christensen RD. Reference ranges for hematocrit and
blood hemoglobin concentration during the neonatal period: data from a multihospital health
care system. Pediatrics 2009;123:e333-e337.
Nicolaides KH, Thilaganathan B, Mibashan RS. Cordocentesis in the investigation of fetal
erythropoiesis. Am J Obstet Gynecol 1989;161:1197-200.
Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective randomized trial of early
versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams.
Pediatrics 2000;106:700-06.
Irigoyen M, Davidson LL, Carriero D, Seaman C. Randomized, placebo-controlled trial of iron
supplementation in infants with low hemoglobin levels fed iron-fortified formula. Pediatrics
1991;88:320-26.
Heese HD, Smith S, Watermeyer S, Dempster WS, Jakubiec L. Prevention of iron deficiency
in preterm neonates during infancy. S Afr Med J 1990;77:339-45.
Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm
and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004868.
Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm
and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004863.
Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion
in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004865.
Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay
in clamping the umbilical cord of preterm infants. Neonatology 2008;93:138-44.
Rabe H, Reynolds G, Diaz-Rossello J. Early versus delayed umbilical cord clamping in
preterm infants. Cochrane Database Syst Rev 2004;CD003248.
Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates:
systematic review and meta-analysis of controlled trials. JAMA 2007;297:1241-52.
Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W. Delayed cord clamping in
very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset
sepsis: a randomized, controlled trial. Pediatrics 2006;117:1235-42.
Ultee CA, van der DJ, Swart J, Lasham C, van Baar AL. Delayed cord clamping in preterm
infants delivered at 34 36 weeks' gestation: a randomised controlled trial. Arch Dis Child Fetal
Neonatal Ed 2008;93:F20-F23.
Ceriani Cernadas JM, Carroli G, Pellegrini L, Otano L, Ferreira M, Ricci C et al. The effect of
timing of cord clamping on neonatal venous hematocrit values and clinical outcome at term: a
randomized, controlled trial. Pediatrics 2006;117:e779-e786.
Alagappan A, Shattuck KE, Malloy MH. Impact of transfusion guidelines on neonatal
transfusions. J Perinatol 1998;18:92-97.
163
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
164
Obladen M, Sachsenweger M, Stahnke M. Blood sampling in very low birth weight infants
receiving different levels of intensive care. Eur J Pediatr 1988;147:399-404.
Nexo E, Christensen NC, Olesen H. Volume of blood removed for analytical purposes during
hospitalization of low-birthweight infants. Clin Chem 1981;27:759-61.
Kakaiya RM, Morrison FS, Rawson JE, Lotz LL, Martin JW. Pedi-pack transfusion in a
newborn intensive care unit. Transfusion 1979;19:19-24.
Ringer SA, Richardson DK, Sacher RA, Keszler M, Churchill WH. Variations in transfusion
practice in neonatal intensive care. Pediatrics 1998;101:194-200.
Widness JA, Madan A, Grindeanu LA, Zimmerman MB, Wong DK, Stevenson DK. Reduction
in red blood cell transfusions among preterm infants: results of a randomized trial with an inline blood gas and chemistry monitor. Pediatrics 2005;115:1299-306.
Lin JC, Strauss RG, Kulhavy JC, Johnson KJ, Zimmerman MB, Cress GA et al. Phlebotomy
overdraw in the neonatal intensive care nursery. Pediatrics 2000;106:E19.
Madan A, Kumar R, Adams MM, Benitz WE, Geaghan SM, Widness JA. Reduction in red
blood cell transfusions using a bedside analyzer in extremely low birth weight infants. J
Perinatol 2005;25:21-25.
Parkman R, Mosier D, Umansky I, Cochran W, Carpenter CB, Rosen FS. Graft-versus-host
disease after intrauterine and exchange transfusions for hemolytic disease of the newborn. N
Engl J Med 1974;290:359-63.
Hall TL, Barnes A, Miller JR, Bethencourt DM, Nestor L. Neonatal mortality following
transfusion of red cells with high plasma potassium levels. Transfusion 1993;33:606-09.
Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ et al. Randomized trial
of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants.
Pediatrics 2005;115:1685-91.
Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA et al. The
Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a
restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight
infants. J Pediatr 2006;149:301-07.
Whyte RK, Kirpalani H, Asztalos EV, Andersen C, Blajchman M, Heddle N et al.
Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to
restrictive or liberal hemoglobin thresholds for blood transfusion. Pediatrics 2009;123:207-13.
Brooks SE, Marcus DM, Gillis D, Pirie E, Johnson MH, Bhatia J. The effect of blood
transfusion protocol on retinopathy of prematurity: A prospective, randomized study.
Pediatrics 1999;104:514-18.
Ross MP, Christensen RD, Rothstein G, Koenig JM, Simmons MA, Noble NA et al. A
randomized trial to develop criteria for administering erythrocyte transfusions to anemic
preterm infants 1 to 3 months of age. J Perinatol 1989;9:246-53.
Strauss RG. Neonatal anemia: pathophysiology and treatment. Immunol Invest 1995;24:34151.
Brown MS, Berman ER, Luckey D. Prediction of the need for transfusion during anemia of
prematurity. J Pediatr 1990;116:773-78.
Joshi A, Gerhardt T, Shandloff P, Bancalari E. Blood transfusion effect on the respiratory
pattern of preterm infants. Pediatrics 1987;80:79-84.
Andriessen P, Kollee LA, van Dijk BA. [Effect of age of erythrocyte concentration
administered to premature infants: a retrospective study]. Tijdschr Kindergeneeskd
1993;61:82-87.
Widness JA, Seward VJ, Kromer IJ, Burmeister LF, Bell EF, Strauss RG. Changing patterns
of red blood cell transfusion in very low birth weight infants. J Pediatr 1996;129:680-87.
Patten E, Robbins M, Vincent J, Richardson J, Hokanson J. Use of red blood cells older than
five days for neonatal transfusion. J Perinatol 1991;11:37-40.
Luban NL. Massive transfusion in the neonate. Transfus Med Rev 1995;9:200-14.
Petaja J, Johansson C, Andersson S, Heikinheimo M. Neonatal exchange transfusion with
heparinised whole blood or citrated composite blood: a prospective study. Eur J Pediatr
2000;159:552-53.
38.
39.
40.
41.
Jackson JC. Adverse events associated with exchange transfusion in healthy and ill
newborns. Pediatrics 1997;99:E7.
Maisels MJ, Li TK, Piechocki JT, Werthman MW. The effect of exchange transfusion on
serum ionized calcium. Pediatrics 1974;53:683-86.
Ip S,Chung M,Kulig J et al .An evidence-based review of important issues concerning
neonatal hyperbirubinemia.Pediatrics 2004; 114: 130-153.
Khodabux CM,Hack KEA,von Lindern JS,Brouwers H,Walther FJ,Brand A . A comparative
cohort study on transfusion practice and outcome in two Dutch tertiary neonatal centres
Transfusion Medicine, 2009, 19, 195201
Literature 4.6
1.
2.
3.
4.
5.
Cobain TJ, Vamvakas EC, Wells A, Titlestad K. A survey of the demographics of blood use.
Transfus Med. 2007 Feb;17(1):1-15.
Gibson BE, Todd A, Roberts I, Pamphilon D, Rodeck C, Bolton-Maggs P, Burbin G, Duguid J,
Boulton F, Cohen H, Smith N, McClelland DB, Rowley M, Turner G; British Commitee for
Standards in Haematology Transfusion Task Force: Writing group. Transfusion guidelines for
neonates and older children. Br J Haematol. 2004 Feb;124(4):433-53.
Slonim AD, Joseph JG, Turenne WM, Sharangpani A, Luban NL. Blood transfusions in
children: a multi-institutional analysis of practices and complications. Transfusion. 2008
Jan;48(1):73-80.
Stainsby D, Jones H, Wells AW, Gibson B, Cohen H; SHOT Steering Group. Adverse
outcomes of blood transfusion in children: analysis of UK reports to the serious hazards of
transfusion scheme 1996-2005. Br J Haematol. 2008 Apr;141(1):73-9.
Wong EC, Perez-Albuerne E, Moscow JA, Luban NL. Transfusion management strategies: a
survey of practicing pediatric hematology/oncology specialists. Pediatr Blood Cancer. 2005
Feb;44(2):119-27.
165
In acute blood loss, depending on the volume and speed of the blood loss on the one hand
and the physiological ability to compensate on the other hand, symptoms occur based on
loss of circulating volume.
5.1.1 Estimating blood loss based on symptoms
A reasonable estimate of the loss of circulating volume in an average adult can be made
based on the clinical symptoms according to ATLS categorisation (American College of
Surgeons 2008), as shown in table 5.1.1. There is a slightly different score for children, with
only three shock classifications and different volumes.
166
Class 2
Class 3
Class 4
< 750
750-1500
1500-2000
>2000
(70 kg adult)
< 15%
15 30%
30 40%
> 40%
Heart rate
< 100
>100
>120
>140
Blood pressure
Normal
Normal
Pulse pressure
Normal
Respiration frequency
14-20
20-30
30-40
>40
>30
20-30
5-15
<5
CNS
Agitated
Anxious
Confused
Drowsy
167
5.2
Most patients with acute anaemia have or had blood loss, but not massive bleeding. Their
blood loss can be compensated by physiological mechanisms and/or therapy. The
erythrocyte transfusion policy in this situation can be based on Hb values.
In patients with burn wounds who were transfused at either an Hb < 6 mmol/L or an Hb < 4
mmol/L respectively, no difference was found in survival, hospital stay or cardiac
decompensation (Sittig 1994). In a study in patients undergoing coronary bypass surgery,
one group received a transfusion at a haematocrit (Ht) < 0.32 L/L and the other group at an
Ht < 0.25 L/L. No difference was found in fluid requirement, haemodynamic parameters or
in-hospital complications (Johnson 1992). A randomised study in patients undergoing aortic
valve replacement surgery, showed no difference in survival or acid-base abnormalities
between the group receiving blood at an Hb of 5.5 mmol/L and the group receiving blood at
an Hb of 4 mmol/L (Lilleaasen 1978). The duration of ventilation in intensive care (ICU)
patients did not differ for the group who were transfused at an Hb < 6 mmol/L compared to
the group who received transfusions at an Hb < 4 mmol/L (Hebert 2001). This demonstrates
that a relatively low Hb is well tolerated.
Too liberal transfusion policy can also be harmful. In a prospective randomised study in 838
adult ICU patients who needed (non-leukocyte reduced ECs: see also 5.4.2) transfusions,
the aim was to maintain an Hb between 4.5 and 5.5 mmol/L in the one group and an Hb
between 6 and 7.5 mmol/L in the other group. The group with the higher transfusion trigger
the group receiving more blood suffered significantly more myocardial infarctions and
pulmonary oedema. Transfusion trigger was defined in this case as the Hb at which
erythrocyte transfusions were administered. The 30-day mortality was the same in both
groups, but the mortality was significantly lower in a sub-group of younger patients (< 55
years) and less severe disease, if the Hb was maintained at between 4.5 and 5.5 mmol/L
(Hebert 1999). Various organisations, including the National Institutes of Health, the
American College of Physicians, the American Society of Anaesthesiologists, the Canadian
Medical Association, the British Committee for Standards in Haematology (Royal College of
Surgeons of England, the Royal College of Physicians and the Royal College of
Anaesthesists) have published guidelines over the past years concerning the use of
erythrocytes. These guidelines assume that a blood transfusion will have few positive effects
at an Hb > 6 mmol/L, that a transfusion is often beneficial at an Hb < 4 mmol/L and that at
an Hb between 4 and 6 mmol/L it depends on patient characteristics whether or not the
transfusion is expected to have a positive effect. The so-called 4-5-6 rule was developed
based on this information, including important factors for the decision to transfuse:
Can the patient compensate for the anaemia (cardiopulmonary status)?
Is there increased use of oxygen (fever, sepsis)?
Are there signs of atherosclerosis (brain, heart, kidneys, intermittent claudication)?
Is there continuous active blood loss and if so how much?
Please refer to table 5.2 for the 4-5-6 rule.
168
Table 5.2: : The 4-5-6 rule for erythrocyte transfusion for acute normovolemic anaemia
Consider a transfusion if the following occurs at an Hb < 4 mmol/L:
acute blood loss in a healthy individual (ASA I, see table 5.1.3) < 60 years, normovolemic,
blood loss at 1 location
Consider a transfusion if one of the following situations occurs at an Hb < 5 mmol/L:
acute blood loss in a healthy individual (ASA I, see table 5.1.3) of > 60 years and
normovolemic, blood loss from 1 location
acute blood loss in healthy individuals < 60 years, normovolemic, bleeding from several
locations (poly-trauma patients)
patient < 60 years, pre-operative, with an expected blood loss > 500 mL
fever
post-operative phase following open heart surgery, uncomplicated
ASA II and ASA III
Consider a transfusion if one of the following situations occurs at an Hb < 6 mmol/L:
ASA-IV patients
patient who is unable to increase the heart minute volume to compensate for haemodilution
septic* and toxic patient
patient with severe lung disease
patient with symptomatic cerebrovascular disease
* See 5.10 for differentiation
Table 5.2 b: ASA criteria
The ASA criteria are:
I
healthy individuals
II
patients with a mild systemic abnormality, without limitation of function
III
patients with a severe function-limiting systemic abnormality
IV
patients with a systemic abnormality that is constantly life threatening
V
patients who are moribund and would probably die within 24 hours with or without surgery
Recommendation 5.2
It is recommended that the so-called 4-5-6 rule (see table 5.2: the 4-5-6 rule) be maintained
as a guideline for an erythrocyte transfusion in acute normovolemic anaemia.
5.3
169
digestive tract bleeding, who meet the ATLS shock classifications III/IV. Resuscitation is
required. However, this is a small category, seen in only a few percent of civilian traumas,
but is more common in military calamities.
The first two definitions of massive blood loss as mentioned above often involve less
rapid blood loss, which is easier to compensate for. With slower blood loss there is usually
no resuscitation situation and a component policy can be implemented based on laboratory
values such as Hb, Ht, platelets and clotting parameters. A compensated situation with
massive blood loss can occur for example peri-operatively or in the intensive care unit.
In both the compensated and decompensated situation, with massive blood loss, a
coagulopathy due to dilution, use of pro-coagulant factors and activation of anti-coagulant
and fibrinolytic factors can further compromise the haemostasis.
Supplementing the lost blood volume with only ECs or physiological saline or colloids causes
a dilution of the clotting factors and platelets. This dilution coagulopathy further
compromises the blood clotting in the bleeding patient.
A loss of 1 1.5 times the circulating blood volume and supplementation with fluids or ECs
alone causes a shortage of clotting factors and a decrease in the fibrinogen level. This is
associated with elongation of the Prothrombin Time (PT) (see table 5.3: Clotting disorders
due to massive blood loss) (Murray 1995, Hippalla 1995). A critical drop in the number of
platelets only becomes evident at a later stage and is reached at a blood loss of more than 2
3 times the circulating blood volume (Murray 1995). However, there is a wide distribution.
The extent and time at which these shortages occur depend partly on the rate of blood loss
(Koopman-van Gemert 1996, Hirschberg 2003).
Table 5.3: Clotting disorders due to massive blood loss
First author
Murray
1995
Hiippala
1995
Koopman-van
Gemert
1996
Geeraedts
2007
170
Study design
Spondylodesis;
blood
compensated
with
concentrates (n = 32)
Results
loss
only 50% loss of Circulating Volume: aPTT (actierythrocyte vated Partial Thromboplastin Time) and PT
(Prothrombin Time) 2x longer, clotting
abnormalities clinically manifest, platelets still
normal
Surgery with a lot of blood loss
Fibrinogen. 1 g/L with loss of 142% CV
(n = 60)
Factor II = 20% with loss of 201% CV
Measurements performed used to
Factor V = 25% with loss of 229% CV
extrapolate when critical limit of clotting Factor VII = 20% with loss of 236% CV
factors would be reached
Platelets < 50 x 109/L with loss of
230% CV
Theoretical mathematical model of the Massive BL 1 litre per accident: rapid;
effect of rapid blood loss (BL) on with 3 litres of BL still 29% plasma proteins
dilution of plasma proteins
remaining
BL of 0.5 litre per accident: slow;
with 5 litres of BL still 24% plasma proteins
remaining
The actual plasma and platelet 82% of the patients were found to have
transfusions given to multi-trauma received about 50% too few platelets and
patients were compared to the plasma. The ratios improved with more RBC
calculated
amount
required
for transfusions. .
optimum haemostasis corrections
In traumatology and with massive blood loss, there is also another type of coagulopathy
disorder, which is often referred to as trauma induced coagulopathy in the literature of the
English-speaking world (Hess 2008, Brohi 2008, Davenport 2009, Fries 2009, Lier 2008,
Ganter 2008, Rossaint 2010). Research on animals and studies in battle situations have
shown that significant tissue trauma particularly in combination with perfusion
abnormalities or low flow situations triggers the endothelium to increase expression of
thrombomodulin. This elevated expression results in the binding of thrombin. Thrombin is
withdrawn from the system and this results in decreased fibrin formation. Activation of
protein C (aPC) results in inactivation of co-factors V and VIII and therefore causes anticoagulation. In addition, aPC amplifies fibrinolysis by inactivation of Plasminogen Activator
Inhibitor type 1 (PAI-1). However, thrombin bound to thrombomodulin can also activate the
Thrombin Activated Fibrinolysis Inhibitor, which results in inhibition of fibrinolysis.
In the case of trauma induced coagulopathy there is probably competition between the
binding of Protein C and TAFI, which can result in various situations. Brohi found an image
particularly of anti-coagulation and hyperfibrinolysis, which suggests that the elevated
inactivation of PAI-1 is clinically more significant than the activation of TAFI.
Ganter showed that exocytosis of Weibel-Palade bodies takes place with this type of
bleeding, which contain among others vWF (von Willebrand Factor) and angiopoietin 2,
which in turn correlates with increased complement activation and endothelial dysfunction.
In addition, a tissue-(plasminogen)activator is released with extended hypotension, acidosis
and ischaemia (Lier 2008). Liver function abnormalities, consumption of clotting factors,
activated plasmin and fibrin breakdown components contribute to the further deterioration of
haemostasis. Furthermore, the colloid plasma expanders particularly dextran and high
molecular weight HES are known to compromise haemostasis with more blood loss via a
decrease in vWF. This phenomenon should be taken into consideration with the infusion of
all colloids in large quantities (for example > 1.5 L). This is even more applicable if there are
pre-existing abnormalities in haemostasis (Levi 2010).
The vicious circle that is created in this is also referred to as The bloody vicious circle. It
has been demonstrated that these clotting abnormalities are difficult to correct. Recovery of
the hypoperfusion is probably the first point of intervention (Brohi 2009).
The hypothermia (decrease in core body temperature < 35 C) that often occurs in polytrauma patients can perpetuate blood loss by influencing clotting and acidosis. Hypothermia
causes a strongly decreased functioning of both the clotting factors and the platelets (Mc
Donald 2008, Tieu 2007, Fries 2002).
5.3.1 Massive blood loss: the decompensated/hypovolemic shock situation
Particularly in the case of the last definition of massive blood loss as mentioned above
(blood loss > 150 mL/minute in adult patients), there is a life threatening situation due to
exsanguination. These are the situations in which rapid (within 1 hour, the so-called golden
hour) resuscitation is of great importance for survival. This situation is the most well known
in the case of massive uncontrolled blood loss in multi-trauma patients and battle field
situations. This also occurs in the case of large gastro-intestinal, obstetric and arterial
haemorrhages. The policy is aggressive, pragmatic, pro-active and based on an estimate of
the blood loss that has already occurred and is still expected to occur (Geeraedts 2009).
171
The recognition and treatment of patients with uncontrolled blood loss is essential and falls
under shock/resuscitation protocols. The European guideline on this subject (Rossaint 2010)
is a usable example of this.
Please refer to table 5.1.1 in paragraph 5.1.1 for clinical recognition. The haemodynamic
reaction to intravenous filling is also an indication for the existing deficit in circulating volume.
Laboratory values usually lag significantly behind the rapidly changing condition in the case
of persistent bleeding. However, laboratory tests should be performed as soon as possible,
even if only to have the initial data to allow for better estimates of the situation. The base
excess and the lactate level are important values used to estimate the extent of
hypoperfusion and the degree of shock.
The infusion and transfusion policy in the initial phase is based on an estimate of the
circulating volume lost and still expected to be lost until the bleeding has been stopped or
can be controlled. This phase should be implemented as soon as possible after the bleeding
or the trauma occurs and usually takes place at the site where the trauma occurred, during
transport to the hospital, in the Emergency Department or early on during corrective surgery.
Optimisation of the circulating volume and the haemostasis so that the bleeding can be
stopped most effectively are key points in this.
172
Conclusions 5.3.1.1
Resuscitation and damage control surgery are central in massive blood loss
in poly-trauma patients (decompensated situation).
Level 3
Level 3
C
D
Level 3
Rossaint 2010
Level 3
Beekley 2008
Level 3
5.3.1.2 The blind transfusion policy for uncontrolled blood loss: estimated correction of the
circulating volume and haemostasis
In the case of a severe uncontrolled bleed in a patient, a blind transfusion policy must be
started based on clinical symptoms; firstly to prevent hypovolemia, but also to prevent further
compromise of the clotting and haemostasis due to dilution and coagulopathy. This can be
achieved by transfusing erythrocytes, platelets and plasma. In addition to platelets and
plasma, erythrocyte transfusions also play an important haemostatic role. Erythrocytes
mediate the radial transport of platelets to the vascular wall and the co-activation of platelets
by ADP adenosine-di-phosphate) release. At a haematocrit of < 0.3 L/L, the platelet
adhesion is decreased particularly in the vascular bed with high flow speeds (Valeri
2000, Anand 1994, Blajchman 1994, Escolar 1988, Nunez 2009). This decrease will become
greater as the Ht becomes lower (Hardy 2004).
173
A number of studies have appeared in the last few years that concluded that in addition to
the basis measures of resuscitation a transfusion policy with set ratios between
erythrocytes/plasma/platelets increases survival. There are indications that this is due to
prevention and/or correction of the dilution coagulopathy (Beekley 2008, Gonzalez 2007,
Hardy 2004, Holcomb 2008, Johansson 2009, Johansson 2010).
In the study by Johansson (2009), for example, the following transfusion schedule was used:
5 erythrocytes units: 5 plasma units: 2 platelet units (from 5 donors) in bleeding patients who
received > 10 erythrocyte units/24 hours. For the Dutch situation this equates to a ratio of 3:
3: 1. This strategy of administering several components is usually referred to as multicomponent transfusions or as the administration of transfusion packages (Madjdpour 2006,
Hirschberg 2008, Holcomb 2008).
Apart from the logical reasoning that this strategy proactively prevents haemostatic dilution
in massively bleeding patients, these studies do not clearly show which volume of
fluid/colloids or erythrocyte transfusion should be started with. It is also not clear which ratios
of erythrocytes to plasma are optimum. These ratios are based on retrospective studies
(Borgman 2007, Ho 2005, Murad 2010, Roback 2010, Johansson 2010, Saltzherr 2011)
where as mentioned large amounts of erythrocytes and fluids have already been
administered. Studies of battle field situations also use fresh full blood transfusions or
erythrocyte transfusion < 15 days old. The improved survival due to a transfusion policy with
a relatively high plasma-erythrocyte ratio has also not been confirmed in all situations of
massive blood loss (Scalea 2008, Dirks 2010). Finally, there is discussion about whether the
association of a high ratio of plasma-erythrocytes with improved survival is the result of
improved survival (bias) instead of the other way around (Snyder 2009).
Prospective randomised research is desirable before definitive exact recommendations can
be made (Johansson 2010).
Conclusions 5.3.1.2
Multi-component transfusions in patients with massive blood loss can often
have underestimated dilution coagulopathy.
Level 3
C
Level 3
Level 3
174
Level 3
5.3.2 Transfusion policy for massive blood loss in the compensated situation
In a compensated situation, the policy must be tailored to the laboratory values as soon as
possible. Transfusion of individual components should also be implemented again.
5.3.2.1 Erythrocyte transfusion policy for massive blood loss in the compensated
situation
Massive blood loss can be tolerated for a long period if the speed of blood loss is relatively
slow. If a normovolemic (and oxygenated) state can be maintained, the patient will not go
into shock and this is called a compensated situation. The lowest acceptable limit for acute
anaemia due to blood loss has not been determined in humans, because this depends on
the speed of blood loss and the physiological capacity and the therapeutic measures to
accommodate for the blood loss. The Hb value is only reliable once the circulating blood
volume has been restored.
If the blood loss has been controlled by optimising haemostasis, the erythrocyte mediated
oxygen transport becomes the major factor in the policy. However, it is not yet possible to
measure accurately the transfusion-related improvement of low oxygen transport and tissue
oxygenation. The oxygen extraction ratio (O2ER) was examined as a possible surrogate
marker (Orlov 2009). However, the O2ER is only a measure of the systemic oxygen
extraction. As the local (from organ to organ) oxygen extraction at a tissue level (particularly
in the case of sepsis and ischaemic multiple organ failure) can differ from the systemic
oxygen extraction, it may be necessary in future to consider basing the decision to transfuse
and the monitoring of the efficacy on oxygenation measured in target organs (Stowell 2009).
There are data available about the critical limits for tissue oxygenation in experiments with
acute normovolemic haemodilution; this is a compensated situation with corrected circulating
volume (normovolemia), good oxygenation and normothermia. Based on these data, there
are indications that the tissue oxygenation generally remains adequate down to an Hb of 3
5 mmol/L. This applies to these circumstances in healthy volunteers, for both the heart
function and the brain function (Weiskopf 1998). Administration of 100% oxygen can
temporarily bridge an Hb deficit of 1 mmol/L. In the case of acute blood loss with another
dilution step to follow it appears to be better not to allow the Hb to drop to 3 mmol/L. This
concentration is mentioned in the literature as the limit below which cerebral function
abnormalities occur (Madjdpour 2006).
175
Conclusions 5.3.2
There are indications that in the compensated situation of massive blood
loss, adequate tissue oxygenation in healthy individuals is generally
guaranteed for both cardiac function and cerebral function to an Hb of 3 5
mmol/L. A prerequisite is that normovolemia, normothermia and oxygen
Level 2
supply are maintained.
B
C
There are indications that the Hb level is reliable as soon as the circulatory
blood volume has been restored.
Level 3
C
Level 3
Madjdpour 2006
Partly due to the limited value of the Hb measurement, particularly in the case of persistent
bleeding, there is little evidence to indicate the Hb concentration at which erythrocytes need
to be transfused. The decision to start a transfusion therefore also depends on the blood
loss already suffered (but often difficult to estimate), the estimated speed of blood loss and
still expected blood loss, as well as the comorbidity such as cardiovascular reserves
(Murphy 2001, Simon 1998, Ekeroma 1997, CMA Expert working group 1997, Hebert 1997,
ASA TFBCT 1996). Also refer to the 4-5-6 rule (table 5.2, paragraph 5.2).
5.3.2.2 Platelet transfusions for massive compensated blood loss
Reviews and guidelines usually recommend to maintain the platelet count > 50 x 109/L with
persistent blood loss and > 100 x 10 9/L in the case of direct vital haemorrhages, for example
intracranial (Fries 2002, McDonald 2008, CMA Expert Working group 1997, Rossaint 2010).
5.3.2.3 Specific clotting-modulating measures for massive blood loss
As far as the clotting parameters are concerned, the aim has long been to achieve aPTT and
PT values up to 1.5x normal and a fibrinogen level > 0.8 g/L. With respect to the frequently
mentioned target value of 0.8 g/L for fibrinogen, this value is probably sub-optimal for
effectively stopping uncontrolled blood loss. As a pre-emptive measure, an initial
determination of fibrinogen at 0.8 1.0 g/L in a bleeding patient should always be
considered too low, as this value will decrease further due to dilution and use (FengerEriksen 2008, Thomas 2010, Bolliger 2010). In a bleeding patient taking into consideration
the delay in determination a measured fibrinogen of 1.5 g/L is probably already an
indication for specific fibrinogen elevating and clotting factor correcting treatments. It is
becoming increasingly accepted that in the case of a large loss of circulating volume the
coagulopathy (due to loss and dilution) can be severe and in particular fibrinogen decreases
to critical levels sooner than other clotting factors (Chowdhurry 2004, Corazza 2000, Murray
1995, Hiipala 1995). Based on a mathematical model, it appears that fibrinogen particularly
176
if the pre-dilution initial value is on the low side of normal is the first factor to fall below the
critical value for normal haemostasis in the case of normovolemic haemodilution (Singbartl
2003). The effect of the dose can be calculated (Solomon 2010). A pilot study of
cardiothoracic surgery patients suggested that with dosage based on the result of TEM or
TEG could result in a more than 50% decrease in the use of clotting factors (Westbrook
2009).
Of course, medicines that inhibit haemostasis such as heparin, coumarins and platelet
inhibitors should be stopped (temporarily) or reduced.
Conclusions 5.3.2.3
Level 3
Level 3
Fibrinogen preparations are usually not necessary with a multi-component transfusion policy
(so-called transfusion packages with set ratios erythrocytes/plasma/platelets), provided
these are used aggressively and in a timely manner. However, the advice is increasingly to
provide extra and faster compensation of the clotting-dependent haemostasis if surgical
haemostasis cannot be achieved in the short term.
The use of anti-fibrinolytics (tranexamic acid) appears to have a positive effect on mortality
due to massive blood loss with severe trauma. A recent multi-centre RCT (CRASH-2) of
trauma patients revealed that the administration of tranexamic acid resulted in a significant
reduction of both overall mortality and mortality due to bleeding (CRASH-2 trial collaborators
2010). However, confirmation of this in a setting more similar to that in the Netherlands is
desirable before a definitive recommendation of tranexamic acid in trauma patients.
The administration of 4-factor concentrate or recombinant factor VIIa as clotting factor at an
early stage of obvious dilution coagulopathy was also considered, but there are no studies
that show a favourable effect. Also refer to Chapter 8.1.3.6 for the possible use of
recombinant factor VIIa for massive blood loss.
177
Conclusion
Level 2
There are indications from a large RCT that tranexamic acid provides a
reduction in overall mortality and mortality due to bleeding with severe
trauma. Research to confirm this in a setting more similar to the Dutch
situation is recommended, focusing on thrombotic side effects.
A2
When interpreting laboratory tests (Hb, Ht, platelets, aPTT, PT, fibrinogen) particularly in
the case of persistent blood loss one must take into account the fact that these values lag
behind the clinical situation. Point of care determinations should, in theory, limit this delay.
Retrospective studies found that the use of blood components decreased if thromboelastography (TEG) was used to direct the transfusion policy (Johansson 2009, Anderson
2006). It should be noted that directing the transfusion policy based on thromboelastography/elastometry has never been validated.
It is crucially important to have a good agreement with the laboratory about the
communication and the procedure to be followed for massive blood loss. A massive blood
loss protocol and the agreement of a telephone number, on which the laboratory and the
ICU/OR can maintain direct contact, have been recommended in various guidelines
(Stainsby 2000, Rossaint 2010, O Keefe 2008).
5.3.3 Side effects of massive transfusions
Clotting factor deficiencies and thrombocytopenia due to dilution
As was discussed in paragraph 5.3, dilution of clotting factors and platelets occurs when only
fluids and erythrocyte transfusions are used. As a result, heamostasis is compromised.
Citrate intoxication
In the case of massive plasma transfusion, citrate intoxication can occur, which is
characterised by hypotension, increase in end ventricular diastolic pressure and increase in
central venous pressure. On an electrocardiogram a prolonged QT interval, widening of the
QRS complex or shallow T-tops due to hypocalcaemia may be seen. In patients with liver
failure, citrate is metabolised more slowly and the risk of hypocalcaemia is greater. It is
therefore recommended to monitor the (ionised) calcium concentration and ECG changes
and supplement calcium if necessary (Vivien 2005, Perkins 2008, Rossaint 2010).
Hyperkalaemia
Potassium release from erythrocytes takes place during storage which raises the potassium
concentration in the storage solution; this should be taken into consideration in the case of
massive transfusions, particularly in patients with renal insufficiency.
178
179
5.4
180
Conclusion 5.4.1
Level
In the case of acute, massive blood loss during pregnancy and surrounding
childbirth in addition to the rapid administration of infusion solutions and
blood components adequate diagnosis and treatment of the underlying
cause are essential. Calamities occur often when an expectative policy is
maintained for too long. In the perinatal situation the occurrence of
disseminated intravascular should be kept in mind
C
Other considerations
If uterotonic agents do not work, external uterine compression, aortic compression or intrauterine tamponade using gauze sponges or a balloon can be used to try to stop the
bleeding. Radiological embolisations can sometimes prevent hysterectomy in the case of
severe arterial bleeding (Kwee 2006). The experience with the latter procedures is based on
the treatment of uterine myomas.
Recommendations 5.4.1
Please refer to the general recommendations for acute massive blood loss in paragraph
5.3.4.
Specific recommendations concerning acute massive blood loss in pregnancy and childbirth
are:
1.
Always consider a disseminated intravascular coagulopathy (DIC) in case of blood
loss and abnormal haemostasis post-partum.
2.
Anticipate severe blood loss in high risk patients (for example, patients with retained
placenta).
3.
Consider the use of a cell saver (autotransfusion) (see also Chapter 8.2.2).
4.
In the obstetric setting particularly in the case of ongoing and uncontrolled bleeding
also consider radiological embolisation or other radiological interventions to prevent
hysterectomy.
5.4.2 Transfusion policy for acute anaemia in the intensive care unit (ICU)
Introduction
Due to the cardiovascular risks of acute anaemia, blood transfusions are an important part of
the treatment of anaemic patients in the intensive care unit (ICU). Critically ill patients may
also be more sensitive to the immunosuppressive and microvascular complications of blood
transfusions. Therefore, it is important to know which transfusion policy is associated with
the lowest mortality and morbidity.
Method
A search was performed for systematic reviews of RCTs that examined the effect of a liberal
versus a restrictive blood transfusion strategy. Based on these reviews, the large (> 200
patients) RCTs were evaluated separately.
181
Results
Of the 16 potentially relevant reviews, three were evaluated in detail. Two reviews were of
good quality, but related to the same set of RCTs. One review by Gould et al performed a
systematic literature search, but no systematic methods were reported (Gould 2007).
Studying the RCTs discussed in the reviews resulted in three studies with > 200 patients.
This turned out to be one large RCT by Hebert et al (1999), in which two additional analyses
reported the effect of the different policies in a specific sub-population within the same trial.
A restrictive transfusion policy (transfusion if Hb < 4.3 mmol/L and subsequently maintaining
the Hb between 4.3 and 5.6 mmol/L), resulted in a similar 30-day mortality rate in ICU
patients when compared to a liberal transfusion policy (trigger < 6.2 mmol/L; maintenance
Hb 6.2 7.4 mmol/L). There may even have been a lower total death rate during hospital
stay (odds ratio (OR) 0.72, confidence interval (CI) 0.50 1.07). There was also marginally
less multi-organ failure in the restrictive group (Gould 2007). Less sick patients (APACHE-II
<=20) and patients < 55 years of age showed improved survival with a restrictive transfusion
policy. A sub-group analysis of 200 trauma patients in this trial by McIntyre et al showed
similar results (OR 0.86, CI 0.34 2.22) (2004). The restrictive strategy also resulted in a
significant reduction in the number of blood transfusions for example in the sub-group of
trauma patients from 5.4 (SD 4.4) units during ICU admission with the liberal strategy to
2.3 (SD 4.3) units in the restrictive group (McIntyre 2004). However, it should be noted that
the erythrocyte component studied by Hebert et al was not leukocyte-reduced, therefore
extrapolation to the Dutch situation may not be possible.
Conclusion 5.4.2
A restrictive transfusion policy with a transfusion trigger of Hb < 7 g/dL (=
4.3 mmol/L) in ICU patients without a compromised cardiac status resulted
in a strong reduction in the use of blood, with a similar or possibly even a
Level 2
lower 30-day mortality when compared to a liberal transfusion policy with
an Hb trigger < 10 g/dL (= 6.2 mmol/L).
A2
Hebert 1999
Other considerations
In retrospective studies such as the so-called CRIT study the number of transfusions is
often correlated to decreased survival (Corwin 2004, Vincent 2002); however, a causal link
should be interpreted with caution with this type of data and always be examined with a
thorough multi-variant analysis. This association may not be present then and death
following transfusion may rather be associated with a patient who was in worse condition to
begin with (Vincent 2008).
However, several studies justify a restrictive policy, although there may still be patients who
require an individualised transfusion regimen. These are patients with existing compromised
tissue perfusion and/or oxygen transport capacity. Cardiac and pulmonary co-morbidity
reduce this capacity and will undoubtedly influence the optimal transfusion trigger in such
patients. Therefore, it is important to continuously check for signs indicating that the
restrictive transfusion policy may be too restrictive.
A possible generally applicable concept was recently described in patients with pre-existing
anaemia prior to cardiac surgery. It was demonstrated that these patients with a lower
182
2.
* These recommendations are compatible with the 4-5-6 rule (see paragraph 5.2)
183
Study
year
population
Design
Level,
Intervention
quality
(I)
Control (C)
Outcome Result
Comments
I vs C
Reviews
Hill, 2002 Children or
Meta-
Carson,
adults
analysis
2002
Major
surgery/ICU
A2,
only
1 restrictive
RR
trigger:
Variation
10
variation
between
RCTs
between
of large RCT
mortality
9
1.02)
7 and 10 g/dL
and 9 g/dL or or Ht 32
Ht 25 30%
40%
A2,
Transfusion
transfusion at 30-day
at Hb < 7.0 Hb
Large RCTs
Hebert,
838 ICU
RCT
1999
patients with Hb
randomisation,
< 9 g/dL
concealment + g/dL
<
10.0 mortality
g/dL
19%
23%
0.72;
blinding?
vs Multi-organ
OR failure
CI marginally
patients
RCT;
A2,
trauma
Hb < 7g g/dL
Hb < 10 g/dL
mortality
of Hebert,
OR
CI 0.34 transfusions,
2.22
1999
no difference
in other
outcomes
Hebert,
357 ICU
2001
patients
RCT;
A2,
cardiovascular
of Hebert,
disease
1999
Hb < 7g g/dL
Hb < 10 g/dL
mortality
OR
1.14; No difference
CI 0.66 in other
1.96
outcomes
5.4.2.1 Special patients on the intensive care unit (ICU): acute anaemia with sepsis
An analysis of the available literature in 2002 resulted in the recommendation that an Hb
trigger of 7 9 g/dL (4.5 5.5 mmol/L) can be maintained for erythrocyte transfusions in
septic patients in the ICU also when circulation has been restored (Dellinger 2008,
Zimmerman 2004). Liberal limits may still be used in special circumstances, such as
simultaneous coronary insufficiency, hypoxaemia, acute bleeding and lactate acidosis
(Dellinger 2008). Prior to the sepsis recommendation in 2008 (Dellinger 2008), a survey of
intensivists in Canada showed that more than 75% already implemented a restrictive policy
(Hb < 80 g/L = 5.0 mmol/L) in early sepsis in ICU patients (McIntyre 2007).
184
Conclusion 5.4.2.1
It is not yet clear whether there is an optimal transfusion trigger for
erythrocyte transfusions in septic patients in the ICU.
Level 3
B
C
Zimmerman 2004
Dellinger 2008, Vincent 2008
Other considerations
Micro-circulatory imaging (under the tongue) has thusfar not shown large effects of
erythrocyte transfusions in sepsis. The capillary perfusion only appears to improve in
patients with abnormal initial values (Sakr 2007). Experiments in animal models show that
particularly the transmyocardial oxygen extraction (O 2ER) and the associated myocardial
metabolism are better conserved with transfusions at higher triggers (Bloos 1999).
In the case of sepsis, the venous mixed saturation (SvO 2) may be used in addition to the Hb
in determining the transfusion trigger (Vallet 2007). For example, a higher Hb trigger is
considered at an SvO2 < 70% (McIntyre 2007).
Sepsis is characterised by severe morbidity with a pathological redistribution of the perfusion
and capillary leakage, resulting in abnormal tissue perfusion. As has been demonstrated in
studies, the latter can probably be negatively influenced by haemodilution, but conversely
this situation is not necessarily positively affected by transfusions. In this setting, it is very
important that the actual transfusion-related improvement of a
decreased oxygen
consumption can be measured. A measure of oxygen use is the oxygen extraction ratio
(O2ER). It was shown that only O2ER values that are too low can be improved by erythrocyte
transfusions, but that transfusions at normal O 2ER values can even negatively influence the
O2ER value (Orlov 2009). However, the O 2ER is only an overall measure of the systemic
oxygen extraction. In the case of sepsis, where there is ischaemia and perfusion
redistribution at tissue level in one or more organs, the oxygen extraction measured locally in
these organs can differ from the systemic value. In the future it may become possible to
measure oxygen consumption in target organs which may in turn be a base for deciding on a
transfusion regimen (Stowell 2009).
Despite the lack of convincing scientific research on the effect of a restrictive transfusion
policy in patients with sepsis, there appear to be enough indicators that point to the benefits
of a more liberal transfusion policy, particularly in the acute unstable phase.
185
Recommendations 5.4.2.1
1.
2.
In the case of acute anaemia in combination with sepsis the use of the Hb value
alone as erythrocyte transfusion trigger is too simple a concept due to the severe
morbidity. At this time it is as yet recommended to maintain an Hb value of 6 mmol/L
as erythrocyte transfusion trigger following the 4-5-6 rule (see paragraph 5.2).
In the case of acute anaemia and sepsis, one can consider including the systemic
oxygen extraction ratio (O 2ER) and/or SvO2 determinations in the decision whether or
not to transfuse and the measurement of the subsequent result. A transfusion should
be considered sooner in the case of lower values. More research is needed to
formulate specific guidelines about this.
186
so much the absolute post-operative Hb value that should determine whether or not to
administer transfusions, but that the decrease in Hb during and after the surgery should also
be taken into consideration.
5.4.3.2 Tolerance for anaemia in non-cardiac surgery patients with cardiovascular
conditions
In a retrospective cohort study of patients who refused a blood transfusion for religious
reasons, Carson et al found that the odds ratio for mortality was 4.3 times higher if the
patient had cardiovascular disease (see table 5.10.2: Relationship between peri-operative
anaemia and cardiovascular conditions). If the Hb was < 3.7 mmol/L, the mortality in patients
with cardiovascular disease was 8 times higher than in patients without cardiovascular
disease (Carson 1996).
In older patients who recently suffered from a myocardial infarction, the mortality increases
significantly when the haematocrit value is lower than 0.3 L/L (Wu 2001).
Table 5.4.3a: Tolerance of anaemia post-CABG
First author
Study set-up
Result
Evidence
class
A2
Johnson
Paone
Bracey
Doak
Spiess
No difference in rehabilitation
No complications
No difference in morbidity,
mortality or fatigue
A2
Robblee
Carson,
2002
Karkouti,
2008
p = 0.006
No difference in lung function B
tests and cardiopulmonary tests
Insufficient evidence to decide on A1
conservative or liberal policy
187
Hajjar 2010
Observational
Mortality 1.3% at Hb > 12 g/dL (7.4 mmol/L); B
cohort: (n = 33.3% at Hb < 6 g/dL (3.7 mmol/L); the
1,958)
mortality increases more than two-fold with a
decrease in Hb > 4 g/dL (2.5 mmol/L).
Conclusions 5.4.3
In cardiac surgery patients, a post-operative Hb of 4.5 mmol/L is not
associated with an increase in post-operative complications, compared to
an Hb > 5.4 mmol/L. The extent of decrease of the postoperative Hb
compared to the pre-operative Hb is possibly associated with a poorer
outcome.
Level 1
A1
A2
B
C
Level 3
There are indications that for coronary artery bypass grafting (CABG)
patients there is no difference in complications between a post-operative
Hb of 3.7 mmol/L compared to 4.3 mmol/L.
B
Level 3
188
Doak 1995
Level 3
Carson 2002
Johnson 1992, Bracey 1999
Paone 1997
Roblee 2002, Karkouti 2008
Wu 2001
There are indications that the risk of myocardial infarction and left ventricle
Level 3
Spiess 1998
There are indications that the odds-ratio for mortality is 4.3 times higher in
patients with cardiovascular disease who refused a blood transfusion than
in patients without cardiovascular disease who refused a blood transfusion.
At an Hb < 3.7 mmol/L, the mortality appears to be 8 times higher in
patients with cardiovascular disease than in patients without cardiovascular
disease.
B
Carson 1996
Other considerations
To summarise, the above-mentioned conclusions were based on old studies in which the
erythrocyte components were not yet leukocyte-reduced. Furthermore, the aggregate of
studies appears to point to a range for an optimal Hb and Ht: both high and lower Hb and Ht
values appear to be associated with higher morbidity. It is particularly difficult to determine
the lower limit of these ranges per individual patient. As already described in paragraph
5.10.1 Transfusion policy in the ICU for acute anaemia and acute anaemia in combination
with co-morbidity, the indication for transfusion is not only based on the Hb value. Due to
the supposed correlation between mortality and the difference between the post-operative
and pre-operative Hb values, the absolute decrease in Hb post-operatively compared to preoperatively should be considered as a transfusion trigger also in patients with cardiovascular
disease.
Recommendations 5.4.3
1.
A critical limit for anaemia cannot be determined for the individual cardiovascularly
compromised patient; an optimal range of Hb values must be taken into
consideration. The 4-5-6 rule (see paragraph 5.2) provides a guideline.
2.
Due to the supposed correlation between mortality and the difference in postoperative versus pre-operative Hb, the absolute Hb decrease post-operative versus
pre-operative should also be included in the decision whether or not to transfuse.
5.4.4 Acute anaemia and cerebral trauma
An isovolemic Hb decrease to Hb values from 4.3 to 3.4 mmol/L showed a clear decrease in
cerebral function (Weiskopf 2006). In healthy volunteers, the cerebral function improveed
after transfusion at Hb values between 3.1 3.7 mmol/L to 5.0 mmol/L (Weiskopf 2005).
A retrospective study found that the mortality in trauma patients with severe cerebral injury
and an Ht < 0.30 L/L was four times higher than in patients with an Ht > 0.30 L/L. However,
Carlson et al demonstrated that patients had better neurological outcomes after longer
periods with an Ht < 0.30 L/L (2006).
McIntyre found that in a sub-group analysis of the results from a previous randomised trial by
Hebert et al (1999), for patients with moderate to severe brain trauma, there was no
189
difference in 30-day mortality and multiple organ failure between a liberal and a restrictive
transfusion policy (2006).
In a prospective study by Zygun et al, 30 patients with severe cerebral trauma were
randomised between transfusion of 2 units of erythrocyte concentrate (EC) in 2 hours at an
Hb trigger of 8, 9 or 10 g/dL (5.0, 5.6 or 6.2 mmol/L). The brain-tissue oxygenation 1 hour
after transfusions was the only primary endpoint for the short term. Transfusions improved
the brain tissue oxygenation in 57% of the patients, with the extent of improvement
correlating to the Hb increase. This improvement was not correlated to the pre-transfusion
Hb. However, the brain metabolism measured as lactacte-pyruvate ratio and the brain pH
as secondary endpoints did not improve with transfusion at these Hb values (Zygun 2009).
Patients with elevated cerebral pressure due to trauma or with a cerebral heamorhage can
theoretically experience damage due to elevated cerebral perfusion caused by
haemodilution (Hebert 1997).
190
Conclusions 5.4.4
Brain functions in healthy volunteers decreased with an isovolemic Hb
decrease to 5 6 g/dL (3.1 3.7 mmol/L) and can be corrected with
Level 2
transfusions.
B
Level 2
Other considerations
In the literature and particularly as far as retrospective studies are concerned it appears
that for patients with cerebral trauma, the initial severity of the clinical situation act as a
confounder to severely cloud the conclusions when the aim is to correlate outcome on the
one hand and Hb, Ht and transfusions on the other hand. Of continuing and great
importance is that low Hb values with haemodilution in healthy volunteers results in
decreased ability to react and memory dysfunction (Zygun 2009). It seems likely that
particularly the damaged brain can be extra sensitive to an Hb < 6 mmol/L.
Recommendation 5.4.4
It is recommended for patients with cerebral trauma to implement transfusion at an Hb below
5 mmol/L with a target value of Hb 6 mmol/L.
5.4.5 Acute anaemia in combination with anaesthesia
Various anaesthetics, analgesics and sedatives have a positive, dosage-related effect on
tissue oxygenation with acute anaemia (Van der Linden 2000/1998, Schou 1997,
Bissonnette 1994, Lugo 1993, Mangano 1992, Shibutani 1983). Analgesia reduces the
oxygen transport (the DO2) and the oxygen consumption (VO2) without decreasing the
oxygen extraction ratio (Ickx 2000, Van der Linden 1994, Boyd 1992, Rouby 1981).
Sedatives reduce the VO2 more than the DO2 (Mangano 1992).
General anaesthesia results in a lowering of the metabolism, which causes oxygen
consumption to decrease by approximately 10%. Local anaesthetics also influence the
micro-circulatory compensation as far as anaemia and hypoxia are concerned. Anaesthetics
affect thermoregulation, resulting in hypothermia (also see Chapter 8: Blood-saving
techniques and medicines, table 8.1.2 Anaesthesiological measures to decrease blood loss)
(Johansson 1999, Bissonnette 1994).
191
5.4.5.1 Decreased tolerance for blood loss with acute anaemia in combination with
anaesthesia
Anaesthetics also affect the compensatory mechanisms activated with acute anaemia. In the
case of severe blood loss, lowering of the viscosity, regional hypoxaemia and humeroneuronal changes that occur during acute anaemia activate a large number of different
compensatory mechanisms that result in a large tolerance of anaemia (Ickx 2000, Van der
Linden 2000, 1998, Habler 1998, Trouwborst 1998, Bissonnette 1994, Boyd 1992,
Trouwborst 1992, van Woerkens 1992, Van der Linden 1990).
In an awake patient with anaemia, the increase in cardiac output (CO) is caused by a
combination of an increase in stroke volume and an elevation of the heart rate and an
increase in oxygen extraction ratio.
In patients with acute anaemia under general anaesthesia, there is a far less pronounced
increase in heartrate; the compensatory mechanism is increase in stroke volume due to an
increase in preload and an increase in oxygen extraction ratio (Ickx 2000).
Under these conditions of activated compensatory mechanisms during severe blood loss,
one should exercise caution with the combination of strongly negative inotropic anaesthetics
or other medications. Animal studies have shown that the use of halothane is associated in a
dose-dependent manner with a smaller increase in cardiac output upon haemodilution. With
the use of anaesthetics, the Hb could also not be lowered as far with haemodilution, and the
oxygen transport became compromised at an earlier stage (Van der Linden 2003).
Conclusions 5.4.5
It is likely that various anaesthetics, analgesics and sedatives have a
dosage-related positive effect on tissue oxygenation in case of acute
anaemia.
Level 2
A2
B
C
192
A2
B
B/C
Other considerations
Under anaesthesia, it is hard to estimate whether a transfusion trigger needs to be adjusted
up or down. On the one hand the tissue oxygen requirement and capillary bleeding tendency
are often influenced favourably under anaesthesia, on the other hand anaesthesia can
compromise the haemodynamic compensation for blood loss.
Recommendations 5.4.5
1.
2.
With acute anaemia under anaesthesia, one should consider more factors than only
a target Hb or Ht. Other parameters that reflect tissue perfusion, such as oxygen
delivery and oxygen consumption should preferably be included in the transfusion
policy.
Research needs to be performed in order to formulate concrete guidelines for this
situation.
193
Although a liberal transfusion policy after hip operations in elderly patients did not result in
improved rehabilitation, a restrictive policy was associated with more cardiovascular
complications and a higher mortality (Foss 2009).
The same was found in a retrospective study in patients who underwent open vascular
surgery and who had a history or were thought to suffer from coronary artery disease
(Dunkelgrn 2008).
Table 5.4.6: Tolerance for post-operative anaemia
First author
After CABG
1
Bracey
Johnson
Spiess
Doak
Paone
Dunkelgrn
2008
Study set-up
Result
No difference in morbidity,
fatigue or wound healing
No difference in rehabilitation
mortality, A2
A2
After orthopaedic
surgery
6
Carson
Systemic review of literature: Trigger
Hip fractures
Hb < 8 g/dL or symptoms versus Hb <
10 g/dL
7
Carson
Retrospective cohort study: (n =
Hip fractures
8.787)
8
Bowditch
Retrospective cohort study: BMI > 30
Primary THP
versus < 26
(n = 80)
194
Evidence
class
After
vascular
surgery
9
Bush
Major
vascular
surgery
10
Shahar
Carotid surgery
After
urological
procedures
11
Hogue
Radical prostatectomy
A2
Case study: (n = 2)
(n = 190)
RCT:
120
elderly
patients Liberal
policy
fewer
cardiovascular A2 ?
randomised Hb 10 vs Hb 8 g/dL
complications 2 vs 10% and less mortality 0
vs 8%
Foss 14
Hip operations
Conclusions 5.4.6
It is likely that in young men with a normal to high-normal body weight, an
Hb down to 4.5 5.0 mmol/L in the post-operative phase does not
negatively influence general recovery.
Level 1
A2
B
C
Level 3
There are indications that the elderly, women and patients with a low body
weight have a greater need for transfusions.
B
Paone 1997
Recommendations 5.4.6
See 4-5-6 rule paragraph 5.2
5.4.7 Blood transfusion guidelines/triggers for children in the intensive care unit
Introduction
There is a large variation in the administration of erythrocyte transfusions in the paediatric
intensive care units (Nahum 2004, Laverdiere 2002). The difference in patient population
between the intensive care units does not provide sufficient explanation. Factors that are
associated with the administration of an erythrocyte transfusion in practice are: anaemia (Hb
< 6 mmol/L), cardiac or severe critical condition (PRISM score > 10 upon admission) and
damage to multiple organs (Armano 2005). Furthermore, it has been described that the
administration of erythrocyte transfusions to children on an intensive care unit is
independently associated with a longer stay in the intensive care unit, longer duration of
ventilation, longer administration of vaso-active medications and a higher mortality (Bateman
2008, Kneyber 2007). It is therefore desirable to come to a guideline based on literature.
195
Method
A search was performed for randomised, controlled trials (RCTs) (since 1985) or
observational studies (since 2001), in which the value of a certain limit or clinically relevant
outcome was compared to another policy. The quality of the studies was evaluated
according to the new Cochrane tool for assessing risk of bias.
Scientific support
One RCT and one observational study were found. The RCT in which only stable severely
ill children without cardiovascular problems participated, revealed that for a liberal strategy
with transfusion at an Hb < 6 mmol/L the occurrence of multi-organ failure was similar to that
of transfusion at an Hb < 4.4 mmol/L (Lacroix 2007). In the observational study performed
in children with extensive burn wounds (approximately 30% of total body surface area)
there was no difference in duration of stay in the hospital and mortality between transfusion
at an Hb < 4.4 mmol/L or transfusion at an Hb < 6.3 mmol/L (Palmieri 2007).
Table 5.4.7
Author
Yea
r
Study
design
Lev
el
Quality
aspects*
Lacroix6
200
7
RCT
A2
historica
l cohort
Palmieri1 200
0
7
Study
population
Interventio
n
Outcome
result
S, A, C, R: OK
Critically ill 637
B:
Blinding children 3
unclear
14
years
old; Hb <
9.5 g/dL
Hb
Threshold
9.5 vs 7
g/dL
No difference
in
multiple
organ
dysfunction
syndrome
(MODS)
or
progression
of
MODS:
absolute risk
reduction
0.4% (CI
4.6, 5.5) after
28 days of
follow-up.
No difference Children
114
in
baseline with
burn 0
severity
and injury
other
characteristics
Hb 7g/dL No difference
vs Hb in length of
10g/dL
stay,
mortality
rates;
traditional
group
had
twice
the
number
of
pulmonary
complications
* S Sequence generation; A Concealment of allocation; B Blinding (of participants, personnel and outcome
assessors); C Completeness of outcome data; R Selective outcome reporting
196
Conclusion 5.4.7
Level 2
Lacroix 2007
Palmieri 2007
Recommendation 5.4.7
For the time being, the same policy that applies to adults can be maintained for children on
the ICU. Please refer to these recommendations in paragraph 5.4.2.
5.4.8 Massive transfusion in the (premature) neonate
The erythrocyte transfusion policy for neonates including triggers is discussed in
paragraph 4.5. This paragraph discusses a number of aspects of massive erythrocyte
transfusion in neonates, because this occurs relatively often in this patient category.
The term massive transfusion in neonates applies to transfusions of > 80 mL/kg < 24 hours
or for a transfusion speed > 5 mL/kg/hour. Massive transfusions are given during exchange
transfusions, priming of the extracorporeal membrane oxygenation (ECMO, used for severe
lung failure) and during cardiac surgery to correct congenital defects. A potassium
concentration of 8 mmol/L or higher causes arrhythmias and is fatal above 10 mmol/L (Hall
1993). Due to the high potassium concentration and the low 2,3-DPG concentration in blood
that has been stored for a longer period, it is recommended in these situations to use
erythrocytes with a maximum storage duration of 5 days (Kreuger 1976).
Conclusion 5.4.8
Level 3
Erythrocyte components that have been stored for more than 5 days are
dangerous for neonates when used in massive transfusions due to the high
potassium concentration and the low 2,3-DPG concentration.
C
Recommendation 5.4.8
In the case of massive transfusions (> 80 mL/kg/ < 24 hours or administration speed > 5
mL/kg/hour) for neonates, erythrocytes < 5 days old should be selected.
197
Shehata 2007
Khanna 2003
Other considerations
Due to the Type and Screen policy (see paragraph 3.3.2, Compatibility study) currently
implemented by most hospitals, it is only necessary to order pre-operative blood
components( notably erythrocytes) for a limited number of procedures and patients (for
example, those with erythrocyte antibodies).
Recommendations 5.4.9
1.
The working group recommends that a hospital drafts written guidelines on when a
Type and Screen should be performed and when pre-operative blood components
should be requested or reserved. These guidelines are called pre-operative blood
order lists.
2.
The implementation and the use of these pre-operative blood order lists should be
evaluated periodically.
Literature 5.1
1.
2.
3.
4.
5.
198
American College of Physicians. Practice strategies for elective red blood cell transfusion.
Ann Intern Med 1992;116:403-6.
American College of Surgeons Committee on Trauma: Advanced trauma life support for
doctors (ATLS) student course manual Chicago, IL: American College of Surgeons, 8 2008.
Brohi. k. e.a. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation
and hyperfibrinolysis. J of Trauma 2008; 64: 1211-1217.
Davenport RA and Brohi K. Coagulopathy in trauma patints: importances of trombocyte
function? Curr Opin Anaesthesiol 2009; 22: 261-65.
Fries D e.a. Time for changing coagulation management in trauma-related massive bleeding.
Cur Opin Anaesthesiol 2009; 22: 267-74
6.
7.
8.
9.
Literature 5.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
199
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
200
Elizalde Jl, Clemente J, Marin JL, Panes J, Aragon B, Mas A, et al. Early changes in
hemoglobin and hematocrit levels after packed red cell transfusion in patints with acute
anemia. Transfusion 1997;37:573-6.
Escolar G, Garrido M, Mazzare R, Castillo R, Ordinas A. Experimental basis for the use of red
cell transfusions in the management of anemic-thrombocytopenic patints. Transfusion
1988;28:406-11.
Fenger-Eriksen C et al. Fibrinogen substitution improves whole blood clot firmness after
dilution with hydroxyethyl starch in bleeding patients ws undergoing radical cystectomy: a
randomized, placebo controlled clinical trial. J.Thromb.Haemost. 2009; 5: 795-802.
Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Srensen B. Fibrinogen
concentrate substitution therapy in patints with massive haemorrhage and low plasma
fibrinogen concentrations. Br J Anaesth. 2008 101:769-73.
Fowler R, Pepe PE. Fluid resuscitation of the patint with major trauma. Curr Opin
Anaesthesiol 2002;15:173-8.
Fries D, Innerhoefer P, Schobersberger W. Coagulation management in trauma patints. Curr
Opin Anaesthesiol 2002;15: 217-23.
Geeraedts LM Jr, Demiral H, Schaap NP, Kamphuisen PW, Pompe JC, Frlke JP. 'Blind'
transfusion of blood products in exsanguinating trauma patients. Resuscitation.
2007;73(3):382-8.
Geeraedts LM Jr, Kaasjager HA, van Vugt AB, Frlke JP. Exsanguination in trauma: A review
of diagnostics and treatment options. Injury. 2009;40(1):11-20
Gonzalez EA,Moore FA Holcomb JB, Miller CC, Kozar RA, Todd SR, Cocanour CS, Balldin
bc, McKinley BA. Fresh frozen plasma should be given earlier to patints requiring massive
transfusion. J Trauma 2007;62:112-119.
Haisjackl M, Luz G, Sparr H, Gemann R, Salak N, Griesenecker B, et al. The effects of
progressive anemia on jejunal mucosal and serosal tissue oxygenation in pigs. Anesth Analg
1997;84:538-44.
Hardy JF, Moerloose de P, Samama M. Massive transfusion and coagulopathy:
pathophysiology and implications for clinical management. Can J Anesth 2004 51 (4): 293310.
Hebert PC, Blajchman MA, Cook DJ, Yetisir E, Wells G, Marshall J, et al. Do blood
transfusions improve outcomes related to mechanical ventilation? Chest 2001;119:1850-7.
Hebert PC, Hu LQ, Biro GP. Review of physiologic mechanisms in response to anemia. Can
Med Assoc J 1997;156(11 Suppl):S27-40.
Hiipala et al. Hemostatic factors and replacement of major blood loss with plasma poor red
cell concentrates. Anesth.Analg. 1995; 81: 360-365
Hiippala S. Replacement of massive blood loss. Vox Sang 1998;74(Suppl 2):399-407.
Hirschberg et al. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a
computer simulation The J.of Trauma, 2008; 54:454-463
Ho AM et al. A Mathematical model for fresh frozen plasma transfusion strategies during
major trauma resuscitation with ongoing hemorrhage Can. J. Surg 2005 48 470-478
Holcomb JB Increased plasma and platelet to red blood cell ratios improves outcome in 466
massively transfused civilian trauma patints.. Annals of Surgery 2008; 3: 447-458
Holcomb JB, Jenkins D, Rhee P, Johannigman J, et al. Damage control resuscitation: Directly
adressing the early coagulopathy of trauma J Trauma2007;62:307-310
Johansen K, Kohler TR, Nicholls SC, Zierler RE, Clowes AW, Kazmers A. Ruptured
abdominal aortic aneurysm: the Harborview experience. J Vasc Surg 1991;13:240-5,
discussion 245-7.
Johansson et al. Effect of haemostatic control resuscitation on mortality in massive bleeding
patints: a before and after study. Vox Sanguinis 2009 96:111-118
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
Johansson PI, Stensballe J Hemostatic resuscitation for massive bleeding: the paradigm of
plasma and platelets--a review of the current literature. Transfusion. 2010;50(3):701-10.
Johnson RG, Thurer RL, Kruskall MS, Sirois C, Gervino EV, Critchlow J, et al. Comparison of
two transfusion strategies after elective operations for myocardial revascularisation. J Thorac
Cardiovasc Surg 1992;104:307-14.
Kaasjager HAH, Kamphuisen PW, Frolke JP. Massaal bloedverlies bij trauma. Hematologie
Actueel 2001;2:2.
Koopman-van Gemert AWMM. Hemodilution, what is right? Transplant Proc 1996;28:2934-6.
Levi M, de Jonge E. Clinical relevance of the effects of plasma expanders on coagulation.
Sem. Thromb. Hemost. 2007; 33: 810-15.
Lilleaasen P, Stokke O. Moderate and extreme hemodilution in open-heart surgery: fluid
balance and acid-base studies. Ann Thorac Surg 1978;25:127-33.
Madjdpour C, Heindl V, Spahn DR. Risks, benefits, alternatives and indications of allogeneic
blood transfusions. Minerva Anesthesiol. 2006; 72 (5): 282-98.
Madjdpour C, Spahn DR, Weiskopf RB. Anemia and perioperative red blood cell transfusion:
a matter of tolerance. Crit Care Med 2006; 34 (suppl 5): S102-8
Martin RR, Byrne M. Postoperative care and complications of damage control surgery. Surg
Clin N Am 1997;77:929-42.
Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, et al. Recombinant
activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001;51:431-8.
McDonald V,Ryland K. Coagulopathy in trauma: optimising haematological status. Trauma
2008;10:109-123
McIntyre L, Hebert PC. To transfuse or not in trauma patint: a presentation of the evidence
and rationale. Curr Opin Anaesthesiol 2002;15:179-85.
Murad MH,Stubbs JR,Gandhi MJ,Wang AT,Paul A,Erwin PJ,Montori VM,Roback JD.The
effect of plasma transfusion on morbidity and mortality: a systematic review and metaanalysis.Transfusion 2010;50:1371-83
Murphy MF, Wallington TB. Guidelines for the clinical use of red cell transfusions. Br J
Haematol 2001;113:24-31.
Murray DJ, Pennell BJ, Weinstein SL, Olson JD. Packed red cells in acute blood loss:
dilutional coagulopathy as a cause of surgical bleeding. Anesth Analg 1995;80:336-42.
Nunez TC, Voskresensky IV, Dossett LA, Shinal R, Dutton WD, Cotton BA. Early prediction of
massive transfusion in trauma: Simple as ABC ( Assessment of Blood Consumption)? J
Trauma 2009; 66:346- 352
OKeefe T, Refaai M, Tchortz K, Forestner JE, Sarode R. A massive transfusion protocol to
decrease blood component use and costs 2008; 143 (7): 686-690
Orlov D et al The clinical utility of an index of global oxygenation for guiding red blood cell
transfusion in cardiac surgery Transfusion 2009 49 682-688.
Perkins JG, Cap AP, Weiss BM, Reid TJ, Bolan CD: Massive transfusion and nonsurgical
hemostatic agents. Crit Care Med 2008, 36:S325-339.
Poortman P, Meeuwis JD, Leenen LPH. Multitraumapatinten: de principes van damage
control surgery. Ned Tijdschr Geneeskd 2000;144:1337-41.
Roback JD,Caldwell S,Carson J et al.Evidence-based practice guidelines for plasma
transfusion/Transfusion 2010;50:1227-39
Rossaint et al. Critical Care 2010, 14:R52 Management of bleeding following major trauma:
an updated European guideline
Scalea TM et al. Early aggressive use of fresh frozen plasma does not improve outcome in
critically injured trauma patints. AnnSurg 2008 248 578-584).
Simon TL, Alverson DC, Aubuchon J, Cooper ES, DeChristopher PJ, et al. Practice
parameter for the use of red blood cell transfusions. Developed by red blood cell
201
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
Literature 5.3.2
1.
2.
3.
4.
Literature 5.4.1
1.
Ahonen J, Stefanovicand V, Lassila R. Management of post-partum haemorrhage. Acta
2.
3.
4.
202
5.
6.
7.
8.
9.
10.
11.
12.
13.
Hofmeyr GJ, Mohlala BK. Hypovolaemic shock. Best Pract Res Clin Obstet Gynaecol
2001;15:645-62.
Huissoud C, Carrabin N, Audibert F, Levrat A, Massignon D, Berland M, Rudigoz R-C.
Bedside assessment of fibrinogen level in postpartum haemorrhage by thromblastometry.
BJOG 2009; 116: 1097-1102.
Klapholz H. Blood transfusion in contemporary obstetric practice. Obstet Gynecol
1990;75:940-3.
Kominiarek MA, Postpartum Hemorrhage: A recurring pregnancy complication
Semin.Perinatol.2007 31: 159-166
Kwee et al. Emergency peripartum hysterectomy: a prospective study in the Netherlands. Eur.
J. of Obstetr.and Gynecology and Reproduct. Biol. 2006; 124:187-192
Merciera FJ, Bonnet MP. Use of clotting factors and other prohemostatic drugs for obstetric
hemorrhage. Current Opinion in Anaesthesiology 2010; 23: 310-6.
Nolan TE, Gallup DG. Massive transfusion: a current review. Obstet Gynecol Surv
1991;46:289-95.
Seeley HF. Massive blood loss in obstetrics. In: Chamberlain G (ed). Turnbulls Obstetrics.
2nd edition. London: Churchill Livingstone, 1995. p. 735-46.
Thomas D. Facilities for blood salvage (cell saver technique) must be available in every
obstetric theatre. Int J Obstet Anesth. 2005 Jan;14(1):48-50.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Bloos F et al. Effects of modest anemia on systemic and coronary circulation of septic sheep.
Am.J.Physiol. 1999; 277: H2195-204.
Bracey AW, Radovancevic R, Riggs SA, Houston S, Cozart H, Vaughn WK, et al. Lowering
the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on
patint outcome. Transfusion 1999;39:1070-7.
Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, et al. Effect of anaemia and
cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055-60.
Carson JL, Hill S, Carless P, Hebert P, Henry D. Transfusion triggers: a systematic review of
the literature. Transfus Med Rev 2002; 16(3):187-199.
Corwin HL et al. The CRIT study: anemia and blood transfusion in the critically ill current
clinical practice in the United States. Crit.Care Med. 2004; 32: 39-52.
Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of
severe sepsis and septic shock. Crit.Care Med. 2008; 36: 296-327
Doak GJ, Hall RI. Does hemoglobin concentration affect perioperative myocardial lactate flux
in patients undergoing coronary artery bypass surgery. Anesth Analg 1995;80:910-6.
Goodnough LT, Despotis GJ. Establishing practice guidelines for surgical blood management.
Am J Surg 1995;170(Suppl 6A):S16S-20.
Gould S, Cimino MJ, Gerber DR. Packed red blood cell transfusion in the intensive care unit:
limitations and consequences. Am J Crit Care 2007; 16(1):39-48.
Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, Kalil
Filho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leo WC, Almeida JP,
Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO Jr. Transfusion requirements
after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-67.
Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al. A multicenter,
randomized, controlled clinical trial of transfuson requirements in critical care. N Engl J Med
1999;340:409-17.
Hill SR, Carless PA, Henry DA, Carson JL, Hebert PC, McClelland DB, Henderson KM.
Transfusion tresholds and other strategies for guiding allogeneic blood cell transfusion.
Cochrane Database Syst Rev. 2002;(2): CD002042.
203
13.
32.
Johnson RG, Thurer RL, Kruskall MS, Sirois C, Gervino EV, Crichlow J, et al. Comparison of
two transfusion strategies after elective operations for myocardial revascularization. J Thorac
Cardiovasc Surg 1992;104:307-14.
Karkouti K Wijeysundera DN, Yau TM, McCluskey SA, van Rensburg A, Beattie WS . The
influence of baseline hemoglobin concentration on tolerance of anemia in cardiac surgery.
Transfusion 2008: 48; 666-672
Levy PS, Chavez RP, Crystal GJ, Kim S, Eckel PK, Sehgal LR, et al. Oxygen extraction ratio:
a valid indicator of transfusion need in limited coronary vascular reserve. J Trauma
1992;32:769-73.
Levy PS, Kim S, Eckel PK, Chavez R, Ismail EF, Gould SA, et al. Limit to cardiac
compensation during acute isovolemic hemodilution: influence of coronary stenosis. Am
Physiol Soc 1993;265(1 Pt 2):H340-9.
Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM, SPI research
group. Association of perioperative myocardial ischemia with cardiac morbidity and mortality
in men undergoing noncardiac surgery. N Engl J Med 1990;323:1781-8.
McIntyre L, Hebert PC, Wells G, Fergusson D, Marshall J, Yetisir E et al. Is a restrictive
transfusion strategy safe for resuscitated and critically ill trauma patients? J Trauma 2004;
57(3):563-568.
McIntyre LA et al . A survey of canadian intensivists resuscitation practices in early septic
shock. Crit Care 2007 11 R74
Orlov D et al The clinical utility of an index of global oxygenation for guiding red blood cell
transfusion in cardiac surgery Transfusion 2009 49 682-688
Paone G, Silverman NA. The paradox of on-bypass transfusion thresholds in blood
conservation. Circulation 1997;96(Suppl II):II-205-9.
Parsloe MRJ, Wyld R, Fox M, Reilly CS. Silent myocardial ischaemia in a patint with
anaemia before operation. Br J Anaesth 1990;64:634-7.
Robblee JA, Nathan HJ. Does anemia delay the recovery from major surgery in older
patients? Anesth Analg 2002;93:SCA 39.
Sakr Y et al. Microvascular response to red blood cell transfusion in patients with severe
sepsis. Crit. Care Med. 2007; 35: 1639-1644
Spahn DR, Smith R, Schell RM, Hoffman RD, Gillespie R, Leone BJ, et al. Importance of
severity of coronary artery disease for the tolerance to normovolemic hemoditlution:
comparison of single-vessel versus multivessel stenoses in a canine model. J Thorac
Cariovasc Surg 1994;108:231-9.
Spiess BD, Ley C, Body SC, Siegel LC, Stover EP, Maddi R, et al. Hematocrit value on
intensive care unit entry influences the frequency of Q-wave myocardial infarction after
coronary artery bypass graftin. J Thorac Cariovasc Surg 1998;116:460-7.
Stowell CP. All politics and oxygenation, are local: decision making and red blood cell
transfusion. Transfusion 2009: 49 620-621
Turaga KK et al. A metaanalysis of randomized controlled trials in critically ill patients to
evaluate the dose-response effect of erythropoietin.J.of Intensive Care Med. 2007; 22: 27082.
Vallet B. et al. Physiologic transfusion triggers Best.Pract.Res. Clin. Anaesthesiol.
2007;21:173-81
Vincent JL et al. Anemia and blood transfusion in critically ill patients. JAMA 2002 288: 14991507
Vincent JL et al. Are blood transfusions associated with greater mortality rates ? Results of
the Sepsis occurence in acutely ill patients studyAnesthesiology 2008; 108: 31-39
Wahr JA. Myocardial ischaemia in anaemic patients. Br J Anaesth 1998;81(Suppl 1):10-5.
204
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
33.
34.
35.
36.
Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly
patients with acute myocardial infarction. N Engl J Med 2001;345:1230-6.
Zarychanski et al. Erythropoietin-receptor agonists in critically ill patients: a metaanalysis of
randomized controlled trials. CMAJ 2007; 177: 725-734
Zimmerman JL et al. Use of blood products in sepsis: an evidence based review. Critical care
medicine 2004; 32: s542-547
Cochrane Database Syst Rev. 2002;(2): CD002042. Transfusion tresholds and other
strategies for guiding allogeneic blood cell transfusion. Hill SR, Carless PA, Henry DA,
Carson JL, Hebert PC, McClelland DB, Henderson KM.
Literature 5.4.4
1.
2.
3.
4.
5.
6.
7.
Carlson AP et al. Retrospective evaluation of anemia and transfusion in traumatic brain injury.
J. Trauma 2006; 61: 567 -571
Hebert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion
requirements in critical care. Transfusion requirements in Critical Care Investigators,
Canadian Critical Care Trials Group. N.Eng.J.Med 1999 340 409-417
Hebert PC, Hu LQ, Biro GP. Review of physiologic mechanisms in response to anemia. Can
Med Assoc J 1997;156(11 Suppl):S27-40.
Mc. Intyre LA et al. Effect of a libral versus restrictive transfusion strategy on mortality in
patients with moderate to severe head injury. Neurocrit.Care 2006 5 4-9
Weiskopf RB et al. Fresh blood and aged stored blood are equally efficacious in immediately
reversing anemia induced brain oxygenation deficits in humans. Anesthesiology. 2006
May;104(5):911-20
Weiskopf RB, et al. Acute isovolemic anemia impairs central processing as determined by
P300 latency Clin Neurophysiol. 2005 ;116(5):1028-32.
Zygun DA et al. The effect of red blood cell transfusion on cerebral oxygenation and
metabolism aftger severe tranumatic brain injury. Crit. Care Med 2009; 37: 1074-1078.
Literature 5.4.5
1.
2.
3.
4.
5.
6.
7.
8.
205
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Linden P van der, Wathieu M, Gilbert E, Engelman E, Wautrecht JC, Lenaers A, et al.
Cardiovascular effects of moderate normovolaemic haemodilution during enflurane-nitrous
oxide anaesthesia in man. Acta Anaesth Scand 1994;38:490-8.
Lugo G, Arizpe D, Dominguez G, Ramirez M, Tamariz O. Relationship between oxygen
consumption and oxygen delivery during anesthesia in high-risk surgical patients. Crit Care
Med 1993;21:64-9.
Mangano DT, Silliciano D, Hollenberg M, Leung JM, Browner WS, Goehner P, et al.
Postoperative myocardial Ischemia. Anesthesiology 1992;76:342-53.
Rouby JJ, EurinB, Glaser P, Guillosson JJ, Nafziger J, Guesde R, Viars P. Hemodynamic and
metabolic effects of morphine in the critically ill. Circulation 1981;64:53-9.
Schou H, Perez de Sa V, Roscher R, Larsson A. Nitrous oxide reduces inspired oxygen
fraction but does not compromise circulation and oxygenation during hemodilution in pigs.
Acta Anaesthesiol Scand 1997;41:923-30.
Shibutani K, Komatsu T, Kubal K, Sanchala V, Kumar V, Bizzarri D. Critical level of oxygen
delivery in anesthetized man. Crit Care Med 1983;11:640-3.
Trouwborst A, Bommel J van, Ince C, Henny P. Monitoring normovolaemic haemodilution. Br
J Anaesth 1998;81:73-8.
Trouwborst A, Woerkens van EC, Tenbrinck R. Hemodilution and oxygen transport. Adv Exp
Med Biol 1992;317:431-40.
van der Linden P. et al. Tolerance to acute isovolemic hemodilution. Effect of anesthetic
depth. Anesthesiology 2003; 99: 97-104.
Woerkens EC van, Trouwborst A, Lanschot JJ van. Profound hemodilution: what is the critical
level of hemodilution at which oxygen delevery-oxygen dependent oxygen consumption starts
in an anaesthetized human. Anesth Analg 1992;75:818-21.
Literature 5.4.6
1.
2.
3.
4.
5.
6.
7.
8.
9.
206
Bowditch MG, Villar RN. Do obese patients bleed more: a prospective study of blood loss at
total hip replacement. Ann R Coll Surg Engl 1999;81:198-200.
Bracey AW, Radovancevic R, Riggs SA, Houston S, Cozart H, Vaughn WK, et al. Lowering
the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on
patint outcome. Transfusion 1999;39:1070-7.
Bush RL, Pevec WC, Holcroft JW. A prospective, randomized trial limiting perioperative red
blood cell transfusions in vascular patients. Am J Surg 1997;174:143-8.
Carson JL, Chen AY. In search of the transfusion trigger. Clinical orthopaedics and related
research 1998;357:30-5.
Carson JL, Duff A, Poses RM, Berlin JA, Lawrence VA, Huber EC, et al. Perioperative blood
transfusion and postoperative mortality. JAMA 1998;279:199-205.
Doak GJ, Hall RI. Does hemoglobin concentration affect perioperative myocardial lactate flux
in patients undergoing coronary artery bypass surgery. Anesth Analg 1995;80:910-6.
Dunkelgrun M, Hoeks SE, Welten GM, Vidakovic R, Winkel TA, Schouten O, van Domburg
RT, Bax JJ, Kuijper R, Chonchol M, Verhagen HJ, Poldermans D. Anemia as an independent
predictor of perioperative and long-term cardiovascular outcome in patients scheduled for
elective vascular surgery. Am J Cardiol. 2008 Apr 15;101(8):1196-200.
Foss NB Kristensen MT, Jensen PS, Palm H, Krasheninnikoff M, Kehlet H The effects of
liberal versus restrictive transfusion thresholds on ambulation after hip fracture surgery.
Transfusion 2009: 49; 227-234.
Hogue CW Jr, Goodnough LT, Monk TG. Perioperative myocardial ischemic episodes are
related to hematocrit level in patients undergoing radical prostatectomy. Transfusion
1998;38:924-31.
10.
11.
12.
13.
14.
15.
Jonsson K, Jensen JA, Goodson WH, Scheuenstuhl H, West J, Hopf HW, et al. Tissue
oxygenation, anemia and perfusion in relation to wound healing in surgical patients. Ann Surg
1991;214:605-13.
Paone G, Silverman NA. The paradox of on-bypass transfusion thresholds in blood
conservation. Circulation 1997;96(Suppl II):II205-9.
Shahar A, Sadeh M. Severe anemia associated with transient neurological deficits. Stroke
1991;22:1201-2.
Slappendel R, Dirksen R, Weber EWG, Bugter MLT, Jack NTM. Zuinig met bloed. Minder
bloedtransfusies door bloedmanagement. Medisch Contact 2001;56:1250-2.
Spiess BD, Ley C, Body SC, Spiegel LC, Stover EP, Maddi R, et al. Hematocrit value on
intensive care unit entry influences the frequency of Q-wave myocardial infarction after
coronary artery bypass grafting. J Thorac Cardiovasc Surg 1998;116:460-7.
Weber EWG, Slappendel R, Schaaf DB van der, Oosting JD. Halvering van het gebruik van
packed cells bij geprotocolleerde indicatiestelling. Ned Tijdschr Orthopaedie 2000;7:10-2.
Literature 5.4.7
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Literature 5.4.8
1.
2.
Hall TL, Barnes A, Miller JR, Bethencourt DM, Nestor L. Neonatal mortality following
transfusion of red cells with high plasma potassium levels. Transfusion 1993;33:606-09.
Kreuger A. Adenine metabolism during and after exchange transfusions in newborn infants
with CPD-adenine blood. Transfusion 1976;16:249-52.
207
Literature 5.4.9
1.
2.
208
Khanna et al. Review of the clinical practice literature on patint characteristics associated
with perioperative allogeneic red blood cell transfusion. Transfusion Medicine Reviews 2003;
17: 110-9.
Shehata N et al. Risk factors for red cell transfusion in adults undergoing coronary artery
bypass surgery: a systemic review. Vox Sang.2007; 93: 1-11.
A platelet count of < 150 x 109/L, has been defined as thrombocytopenia which means that
the patient has a shortage of circulating platelets. If a patient has functionally abnormal
platelets, this is referred to as thrombocytopathy.
Thrombocytopenia and thrombocytopathy can result in bleeding that can vary in severity
from skin bleeds to fatal bleeding. Various grades of severity are used to objectify bleeding.
The WHO classification according to Miller as shown in table 6.1 is relatively simple (Miller
1981).
Table 6.1: WHO classification severity of bleeding with thrombocytopenia
Grade 1
Petechiae, mouth-nose/vaginal
No effect on Hb
bleeding
Grade 2
Severe melaena, haematuria,
Results in Hb decrease
haemoptysis, haematemesis
< 1.2 mmol/L/24 hours
without
transfusion
indication
Grade 3
All bleeding
EC transfusion indication
Grade 4
Fatal bleeding due to
Includes non-fatal cerebral
extent / localisation
or retinal bleeding with loss
of function
209
Classification
Cause
Congenital
Acquired
Use
Micro-angiopathy
DIC
Breakdown
Thrombo-emboli
Immunological
Pooling
Splenomegaly
Haemodilution
Massive
blood
substitution
Extracorporeal circulation
Haemodilution
+/- pathy
Disrupted thrombopoiesis
Aplastic anaemia, MDS 1,
leukaemia
Iatrogenic: chemotherapy /
radiotherapy
HUS
TTP
HELLP
VOD2, aGVHD3 CAPS 4
Sepsis (low grade)
Shock, hypoxia, haemolysis
Amniotic embolism
HIT(T)5 ;
Auto-immune
Medication-mediated
Allo-immune (PTP 6,passive)
Portal hypertension
Malignant infiltration
Extramedullary
haematopoiesis
Trauma, surgery
ECMO 7 cardiac surgery
Perinatal
In neonates, maternal causes (eclampsia, auto or allo platelet antibodies) or foetal
asphyxiation during birth can also play a role immediately post partum (< 72 hours).
Congenital thrombocytopenia or thrombocytopathy such as Glanzmanns thrombasthenia
and storage pool diseases are rare. Thrombocytopenia > 72 hours post partum is often
due to infections.
210
A pregnant woman can suffer from mild (platelets > 80 x 109/L) gestational
thrombocytopenia; this does not require diagnosis or treatment.
Prevention
spontaneous
bleeding
Prevention
during procedures
Bleeding
> grade 2
Congenital
Thrombocytopathy
Haemodilution
Production
disorder
Splenomegaly
Breakdown/
use
Yes
Yes
Yes
Yes*
Consider
Yes
No
Possibility
No
Possibility*
Yes
Yes
Yes
Yes
Yes
6.2
211
Level 2
Andrew 1993
Other considerations
Most guidelines advise maintaining a platelet count of > 50 x10 9/L in neonates with manifest
(intracranial) bleeding. A trigger of > 50 x 10 9/L platelets is recommended for surgical
procedures in neonates (Strauss 2008, Roberts 2008). These recommendations are based
on evidence level C/D. The recommended trigger for prophylactic transfusions varies per
guideline and review. For the sake of uniformity, the working group advises that only the
following triggers be used: 20, 50 and 100 x 109/L.
Recommendation 6.2.1
Table 6.2.1: Platelet threshold values as indication for platelet transfusion in neonates during
the first month of life
Patient groups
20 x 109/L
50 x 109/L
50 x 109/L
20 x 109/L
50 x 109/L
Special circumstances
Exchange transfusion (ET)*, before ET
During extra-corporeal membrane oxygenation
100 x 109/L
9
100 x 10 /L
*If the platelet count is < 100 x 109/L before the ET, then give platelet transfusion half-way through the
ET. If the platelet count is < 50 x 109/L after the ET, then also give a platelet transfusion.
Level 2
Bleeding tendency
The frequency of intracranial haemorrhage (ICH) with FNAIT is 11 25% (Mueller-Eckhardt
1989, Ghevaert 2007). Two large prospective population studies of pregnant women (25,000
in Cambridge, UK (Williamson 1998) and 10,000 in Norway (Jaegtvik 2000)) together
reported two severe ICH and 1 mild ICH (1: 10,000 20,000 pregnancies). Most neonates
show no symptoms, or only petechiae or bleeding from puncture sites. ICH occurs primarily
in utero, mainly in the 3rd term and occassionally before the 20th week of pregnancy. (Radder
2003, Spencer 2001, Bussel 1988, Symington 2010, Kamphuis 2010). In contrast to
erythrocyte allo-immunisation, 50% of first born children are affected by FNAIT (Ghevaert
2007, Spencer 2001). In most cases FNAIT is only diagnosed after the birth of an affected
child. In a subsequent pregnancy of a child with the same HPA antigens, the
thrombocytopenia is usually similar or more severe (Radder 2003, Bussel 1988). Following
the birth of a child with ICH, the chance of ICH in a subsequent HPA-(1a) positive child is
approximately 80%. If a previous child did have thrombocytopenia,but did not have ICH, the
risk of ICH in a subsequent child is estimated at 7 13% (Radder 2003).
213
Conclusion 6.2.2
Level 3
There are indications that after the birth of an HPA-1a positive child with
intracranial haemorrhaging (ICH) the risk of ICH in a subsequent HPA-1a
positive child is approximately 80%. If a previous child did have
thrombocytopenia but did not have ICH, the risk of ICH in a subsequent
child is estimated at 7 13%.
B
Radder 2003
Treatment
The treatment should distinguish between a neonate with unexpected thrombocytopenia and
a pregnancy involving an HPA incompatibility after a previous child with FNAIT.
Diagnostic tests for FNAIT should be started if a full term neonate has thrombocytopenia
without indications for congenital abnormalities, infections, haemolytic disease of the
neonate or auto-immune thrombocytopaenic purpurae (ITP) in the mother. A bleeding
tendency should be transfused according to table 6.2.1 (see paragraph 6.2.1), with the
understanding that HPA compatible platelets should preferably be given whilst awaiting the
results of diagnostic tests (Mueller-Eckhardt 1989). The study by Te Pas showed that in the
case of thrombocytopenia of < 50 x 109/L in full term neonates with FNAIT, HPA matched
platelets provided the fastest and most durable platelet increase. (Te Pas 2007). As a
general rule, Sanquin Blood Supply always has HPA-1a and 5b negative platelet
components available for unexpected cases of FNAIT. Kiefel et al demonstrated in a study of
27 neonates with FNAIT that random transfusions provide a very reasonable short-term yield
and can safely be administered until HPA compatible platelets become available (Kiefel
2006). Other treatment options (corticosteroids, intravenous immunoglobulin (IVIG)) work
more slowly (Allan 2007, Mueller-Eckhardt 1989, Te Pas 2007) and are not recommended
as the treatment of first choice.
If there is known HPA incompatibility and a history of FNAIT, then the mother is generally
treated with intravenous immunoglobulin (IVIG) during pregnancy. This causes the platelet
count of the neonate to increase and decreases the incidence of ICH to such an extent that
this policy is more favourable compared to the risk of an invasive policy with intra-uterine
(HPA compatible) platelet transfusions (Radder 2001, Bussel 1988, Birchal 2003, Berkowitz
2006, van den Akker 2007).
At birth by elective Caesarian section or vaginal delivery HPA compatible platelets must
be available (International Forum Vox Sanguinis 2007, Akker 2007).
Conclusions 6.2.2
Level 3
214
Level 3
Level 3
Recommendations 6.2.2
1.
In the treatment of foetal / neonatal allo-immune thrombocytopenia (FNAIT), a
distinction should be made between a neonate with unexpected thrombocytopenia
and a pregnancy after a previous child with thrombocytopenia due to FNAIT.
2.
Diagnostic tests for foetal / neonatal allo-immune thrombocytopenia (FNAIT) should
be started if a full term neonate has thrombocytopenia without indications for
congenital abnormalities, infections, allo-immune haemolytic disease or autoimmune thrombocytopaenic purpurae (ITP) in the mother. If there is a bleeding
tendency, the neonate should be transfused according to table 6.2.1 (see paragraph
6.2.1). (HPA) compatible platelets should preferably be given (in other words, HPA
negative for the antigen against which the antibody is targeted).
3.
If HPA compatible platelets are not immediately available, random transfusions are
not contra-indicated whilst awaiting HPA compatible transfusions.
4.
In an elective delivery of a child with foetal / neonatal allo-immune thrombocytopenia
(FNAIT), HPA compatible platelet transfusions concentrates should be available
immediately.
5.
Foetal / neonatal allo-immune thrombocytopenia (FNAIT) is preferably treated noninvasively (with intra-uterine transfusions) during the pregnancy.
6.
It is recommended that doctors contact the Leiden University Medical Centre the
national centre for foetal-maternal allo-immune diseases for advice about
treatment options for FNAIT.
215
216
Level 3
In 30% of children born to a mother with IPT, the platelet count will
decrease in the first week after birth thus increasing the risk of bleeding.
C
Level 4
Gernsheimer 2007
Recommendations 6.2.3
1.
If the mother has a history of auto-immune thrombocytopaenic purpura (ITP), the aim
should be to have a non-traumatic birth, as far as possible.
2.
In a neonate born to a mother with IPT, the platelet count should be checked for at
least 5 days post partum to check for the occurrence of thrombocytopenia.
3.
Intravenous immunoglobulin (IVIG) is recommended as the treatment of choice for
neonates with passive idiopathic auto-immune thrombocytopenia (ITP) and platelet
count < 50 x 109/L without clinical bleeding; to be combined with (methyl) prednisolone
in the case of persistent thrombocytopenia.
4.
Platelets transfusion alone or in combination with intravenous immunoglobulin (IVIG)
is recommended for neonates with passive IPT and < 20 x 10 9/L platelets and/or
bleeding.
6.2.4 Dosage and volume of platelet transfusions in neonates
There have been no randomised clinical studies on the optimal dosage of platelet
concentrate and the effects of various platelet components on neonates. Most studies and
guidelines advise a dosage of 10 x 10 9/kg (Strauss 2008). Others suggest giving higher
dosages, namely 20 x 109/kg (Roberts 2008). In order to reduce donor exposure, the advice
is to use platelets obtained from one donor instead of a pooled platelet component (Roberts
2008).
Conclusions 6.2.4
Level 4
There have been no randomised clinical studies on the optimal dosage for
platelets in neonates; experts recommend dosages of both 10 x 109/kg and
20 x 109/kg
D
217
Level 4
Roberts 2008
Other considerations
In the Netherlands, there are three platelet components that can be supplied for neonates:
platelets in plasma (approx. 1 x 109/mL), in storage solution (approx. 0.8 x 10 9/mL) and
hyperconcentrated (approx. 5 x 109/mL) in plasma. There has been no research to
determine which platelet component should preferably be administered to neonates.
Recommendations 6.2.4
1.
2.
3.
6.3
Platelet transfusion policy for thrombocytopenia and thrombocytopathy in
children (> 1 month after full term birth)
The correct platelet transfusion policy can only be selected once the cause of the
thrombocytopenia or thrombocytopathy has been determined and only then can the role of
platelet transfusions be determined.
6.3.1 Platelet transfusion policy in the case of congenital thrombocytopenia and
thrombocytopathy in children
Congenital thrombocytopenia and thrombocytopathy are a rare cause of an increased
bleeding tendency in children. As a result, guidelines for its treatment are mostly based on
case reports, small case series and expert opinion (Bolton-Maggs 2006).
Treatment options consist of anti-fibrinolytic agents (tranexamic acid), desmopressin,
recombination factor VIIa and platelet transfusions. The advice is to maintain a restrictive
policy for platelet transfusions because of the risk of alloimmunisation. Platelet transfusions
should only be given in case of severe bleeding or if the other treatment options are not
effective (Almeida 2003, Bolton-Maggs 2006).
Consideration
Congenital thrombocytopathic diseases are rare. It can be considered to select pre-emptive
HLA identical donors for this small group in case of elective procedures that require platelet
transfusions.
218
Conclusion 6.3.1
Level 3
Bolton-Maggs 2006
Recommendations 6.3.1
1.
2.
219
Conclusions 6.3.2
Level 1
Level 1
Level 4
Stanworth 2004
Recommendations 6.3.2
1.
2.
220
For children in a stable situation with leukaemia being treated with high dose
chemotherapy or after stem cell transplantation, the working group advises a
prophylactic platelet transfusion trigger of 10 x 10 9/L.
In children with leukaemia, being treated with high dose chemotherapy or after stem
cell transplantation and with an increased risk of bleeding due to platelet use as is
the case of sepsis, hyperleukocytosis, a very rapid drop in platelet count or other
abnormalities in haemostasis a platelet transfusion trigger of 20 x 109/L is advised.
6.3.3. Platelet transfusion policy for severe aplastic anaemia (SAA) in children
There is no literature available about platelet transfusions in young children with severe
aplastic anaemia (SAA). There is 1 retrospective analysis performed on 25 adolescents and
adults (aged 15 76 years) (Sagmeister 1999). It appeared safe to follow a restrictive
prophylactic platelet transfusion policy in patients with SAA. A transfusion trigger of < 5 x
109/L is recommended for stable patients and a transfusion trigger of < 10 x 10 9/L is
recommended for sick patients with infections, fever or sepsis. (Sagmeister 1999). The
BCSH (British Committee for Standards in Haematology) advises to maintain a restrictive
policy for platelet transfusions in children with severe aplastic anaemia (Gibson 2004).
However, during treatment with anti-thymocyte globulin (ATG), a transfusion trigger of 20 x
109/L (BCSH 2004) or 30 x 10 9/L (Marsh 2009) is recommended for prophylactic platelet
transfusion. This is due to the increased consumption of platelets during ATG administration
(Gibson 2004). It is advisable not to administer the platelets and ATG simultaneously (Marsh
2009).
Conclusions 6.3.3
Level 3
Level 4
Sagmeister 1999
Other considerations
There are no studies on children with SAA. Therefore, the same recommendations that
apply to adults are made for the time being.
221
Recommendations 6.3.3
1.
2.
3.
222
Conclusions 6.3.4
Level 3
Level 4
Experts are of the opinion that for children with thrombocytopenia due to
disseminated intravascular coagulation (DIC) prophylactic platelet
transfusions should be given at a platelet trigger of 20 x 10 9/L.
D
Level 4
Spahr 2008
Gibson 2004
Experts are of the opinion that the administration of platelet transfusions for
thrombotic thrombocytopaenic purpura (TTP), haemolytic-uraemic
syndrome (HUS) and heparin-induced thrombocytopenia (and thrombosis)
(HIT(T)) results in very little yield and may even result in deterioration of the
clinical situation. In the case of life threatening bleeds due to TTP, HUS or
HIT(T) platelet transfusions can halt the bleeding.
D
Gibson 2004
Recommendations 6.3.4
1.
2.
3.
223
usually aims for a platelet count > 100 x 10 9/L (see paragraph 6.4: adults). According to
American and English guidelines, a bone marrow biopsy can be performed without platelet
transfusion (Schiffer 2001, Gibson 2004).
Conclusion 6.3.5
Level 4
Other considerations
As there is no evidence for other invasive procedures, the recommendations for adults can
be followed (see paragraph 6.4).
Recommendation 6.3.5
There is insufficient literature available concerning the platelet transfusion policy for invasive
procedures and surgical procedures other than lumbar punctures in children with
thrombocytopenia. Therefore, the working group advises that, for the time being, the
recommendations for adults should be followed for such procedures (see paragraph 6.4).
6.3.5.1 Platelet transfusion policy for a lumbar puncture (LP) in the presence of
thrombocytopenia
Most lumbar punctures (LP) with thrombocytopenia are performed on children with
leukaemia for diagnosis of any meningeal metastases and/or for the administration of
intrathecal medication.
The complications that can occur are related to bleeding. Spinal and/or intracranial bleeding
with the risk of neurological damage is rare and also occurs after LPs in children with normal
platelet counts and intact coagulation.
In addition, there is a risk of introducing leukaemic cells into the central nervous system
(CNS) if there are blasts present in the peripheral blood.
There are no prospective studies that examine the platelet trigger when performing LPs in
children. There are retrospective, observational studies and case series. The largest
observational studies on the occurrence of complications with LP and thrombocytopenia
were performed in children with acute lymphatic leukaemia (ALL) (Gaydos 1962).
Van Veen et al performed a retrospective review of 226 ALL patients; 135 patients had a
platelet count < 50 x 109/L and 129 had an LP, of which 72 without transfusion (9 patients
had a platelet count of < 10 x 109/L, 22 patients with 10 20 x 109/L and 41 patients with 21
50 x 109/L). There were no complications (Van Veen 2004). These findings confirm
previous findings by Howard et al: stable children with ALL without blasts in the peripheral
blood and without severe spinal or cranial bleeding can safely undergo LP at a platelet count
of > 10 x 109/L (Howard 2002, 2000).
Gajjar et al compared the chances of survival in 546 children with ALL with traumatic and
non-traumatic LPs. The survival was worse in children with a traumatic diagnostic LP and
224
blasts in the peripheral blood (Gajjar 2000). Howard et al analysed the risk factors for a
traumatic LP based on multiple regression analysis of 5609 LPs in 956 children with ALL.
Fewer traumatic punctures occurred at a platelet trigger > 50 100 x 109/L (Howard 2002).
Conclusions 6.3.5
Level 3
There are indications that for children with acute lymphatic leukaemia
(ALL) and blasts in the peripheral blood at a platelet count of > 50 100
x 109/L, there are fewer iatrogenic metastases of the leukaemia in the
central nervous system (CNS) as a result of a traumatic lumbar puncture
(LP).
C
Level 3
Other considerations
Other factors also play a role, particularly whether general anaesthetic is used or not and the
experience of the surgeon. A higher platelet transfusion trigger can be considered if general
anaesthesia cannot be used when performing an LP in children (please refer to the
Guideline PSA for children in locations outside the OR (NVA, NVK 2010) for the accessory
conditions concerning the use of anaesthesia and/or procedural sedation and/or analgesia
(PSA) when performing an LP) and/or if the physician who performs the LP is
inexperienced.
Recommendations 6.3.5
1.
2.
3.
225
In general, the dosage for children is calculated based on the body weight, using the formula
5 10 x 109 platelets/kg. There is limited data available about the effects of different doses
of platelets on the transfusion outcomes in children (Roy 1973, Norol 1998).
In 1973, Roy et al compared two doses (0.2 versus 0.4 x 10 10 platelets/kg) in children with
acute lymphatic leukaemia (ALL). The yield after 1 hour was 17 and 25 x 109/L
respectively. The incidence of bleeding was the same (Roy 1973).
In 1998, Norol et al examined three different dosages of platelets (medium group: 0.1 x 10 11
platelets/kg), high group: 0.15 x 1011 platelets/kg and extra high group: 0.22 x 10 11
platelets/kg) in 13 children with thrombocytopenia following bone marrow transplantation.
There was a clear-dose effect relationship: the higher the dosage, the greater the increase in
the number of platelets 12 hours after transfusion. The transfusion interval was 2.5 days, 3.4
days and 4.4 days respectively. This study did not examine the risk of bleeding (Norol 1998).
Conclusions 6.3.6
Level 3
In children with acute lymphatic leukaemia (ALL) who were given 0.2 x
1010 platelets/kg or 0.4 x 1010 platelets/kg, the yield after 1 hour was 17 x
109/L and 25 x 109/L respectively. The incidence of bleeding was the same.
B
Level 3
Roy 1973
Norol 1998
Recommendation 6.3.6
The old dosage advice for platelet transfusion in children namely one paediatric unit of 50
to 100 x 109/10 kg (= 5 10 x 109/kg ) is maintained.
6.4
6.4.1 Platelet
transfusion
thrombocytopathy
policy
for
congenital
thrombocytopenia
Congenital platelet function disorders are rare conditions and usually have already been
diagnosed and treated by the paediatrician. In the case of congenital thrombocytopenia /
thrombocytopathy, transfusions for the prevention of spontaneous bleeding are not indicated
due to the risk of allo-immunisation (Fujimori 1999). However, transfusions may be
necessary in the case of bleeding, refractory to other treatments such as desmopressin
226
(DDAVP), tranexamic acid and activated recombinant factor VIIa and for elective
procedures, if medicinal correction of the bleeding time produces insufficient effect (BoltonMaggs 2006, Almeida 2003, 1996, Manco-Johnson 2001, 1996, Mannucci 1997, Weiss
1996, Fujimori 1999).
6.4.1.1 Von Willebrand Disease (vWD)
Von Willebrand Disease (vWD) is the most common congenital coagulation abnormality with
a frequency of approximately 1%. This is a quantitative (types 1 and 3) or qualitative (type 2)
defect of the von Willebrand factor (vWF). vWD type 1 is most common and is treated with
desmopressin and/or vWF + FVIII (Haemate P). There are many sub-types of type 2 vWD
and desmopressin is contra-indicated for type 2B because it can cause platelet aggregation
and thrombocytopenia. Type 2A is treatable with desmopressin. Desmopressin is not
effective for the very rare type 3. Platelet transfusions are very rarely necessary (Mannucci
1997).
Conclusions 6.4.1
Transfusions for the prevention of spontaneous bleeding are not indicated
for congenital thrombocytopenia / thrombocytopathy due to the risk of alloimmunisation resulting in the patient becoming refractory for platelet
Level 3
transfusions.
C
Level 3
Other considerations
Allo-immunisation is extremely undesirable in patients with congenital thrombocytopathy or
thrombocytopenia, since platelet transfusions may be necessary in the event of severe
acute bleeding. The pre-emptive selection of HLA compatible platelets should be considered
for an elective procedure requiring platelet transfusions.
Recommendations 6.4.1
1.
2.
3.
227
Level 3
Stanworth 2004
Other considerations
The meta-analysis by Stanworth based their conclusion that prophylactic use of platelet
transfusions resulted in fewer severe haemorrhages mainly on older studies in which the
use of aspirin cannot be ruled out. Wandt et al (Wandt 2006) studied patients following
autologous stem cell transplantation: these patients are less sick and have only transient
thrombocytopenia compared to the patients from the meta-analysis by Stanworth (Stanworth
2004).
Recommendation 6.4.2.1
Prophylactic platelet transfusions are recommended for patients with thrombocytopenia due
to an acquired production disorder. A therapeutic transfusion policy can be considered for
furthermore healthy patients experiencing a short period of pancytopaenia.
228
6.4.2.2 The platelet transfusion trigger for prophylactic platelet transfusions for the
prevention of spontaneous haemorrage
The only study on the relationship between the platelet count and spontaneous bleeding is a
study in 20 non-transfused patients in whom the loss of erythrocytes in the faeces was
measured in relation to the platelet count. The findings were as follows (Slichter 1978):
- at a platelet count of < 5 x 109 /L: 50 mL 20 mL/day
- at a platelet count of 5 9 x9/L: 9 mL 7 mL/day
- at a platelet count of 10 25 x 109/L < 5 mL/day
The standard platelet transfusion trigger in the United States is 20 x 10 9/L. Observational
cohort studies reported that transfusion triggers lower than 20 x 10 9/L did not result in a
higher incidence and/or increased severity of bleeding (Slichter 1978, Gaydos 1962, Gmur
1991, Wandt 1998, Sagmeister 1999, Gil-Fernandez 1995, Navarro 1998, Lawrence 2001,
Callow 2002, Nevo 2007a).
A retrospective analysis of patients treated with a myelo-ablative allogeneic haematopoietic
stem cell transplant compared patients who were transfused at a platelet transfusion trigger
of 10 x 109/L with a historic group of 170 patients transfused at a trigger of 20 x 10 9/L. In the
lower trigger group there were significantly more patients with deep thrombocytopenia < 10 x
109/L (19% versus 7%). In both cohorts, deep thrombocytopenia was associated with higher
mortality; however, this was not due to bleeding (Nevo 2007). In a retrospective study in
acute myeloid leukaemia (AML) patients, Kerkhoffs et al found an association between
poor post-transfusion yields and a higher non-bleeding related mortality. (Kerkhoffs 2008).
However, it was not demonstrated that increasing the platelet transfusion threshold to 20 x
109/L had any effect on this non-bleeding related mortality. The recent PLatelet transfusion
And DOsis (PLADO) study a randomised study on dosage showed that there was a 25%
risk of bleeding on the same day the platelet count was < 5 x 10 9/L. There was no correlation
between the platelet count and the bleeding risk at a platelet count 10 80 x 109/L
(Slichter 2010).
Four randomised studies in patients treated because of a haemato-oncological malignancy
and/or stem cell transplantation compared transfusion triggers of 10 x 10 9/L and 20 x 109/L
(Heckman 1997, Rebulla 1997, Zumberg 2002) and 10 x 10 9/L and 30 x 109/L (Dietrich
2005). None of the studies showed any difference in incidence of bleeding. The same 3
studies (Heckman 1997, Rebulla 1997, Zumberg 2002) were included in the Cochrane
analysis in 2004. This meta-analysis concluded that equivalence between a trigger of 10 and
20 or 30 x 109/L had not (yet) been demonstrated (Stanworth 2004).
American (ASCO), British (BCSH) and Dutch (CBO) guidelines advise increasing the platelet
transfusion trigger to 20 x 109/L in clinical situations that can promote bleeding (sepsis,
fever, high blast count, extensive endothelial damage, recent bleeding). This has not been
supported by research (ASCO 2001, BCSH 2003, CBO 2004). At least 3 analyses of large
study populations on the risk of bleeding show that it is not the platelet count but the
occurrence of a bleeding in the preceding five days that is the most important risk factor for
bleeding. (Callow 2002, Nevo 2007, Slichter 2004). However, in practice, the transfusion
threshold is increased to 20 x 10 9/L almost everywhere in the case of a severe bleeding.
This can be the reason that bleeding occurs primarily at higher platelet counts in these
analyses.
Blood Transfusion Guideline, 2011
229
The optimal threshold level for platelet transfusions has not been examined for patients who
are taking anti-coagulant medication.
Table 6.4.2: Literature summary of prophylactic transfusion triggers in adults with
thrombocytopenia due to a production disorder
First
author
Rebulla1
Number of
patients
255
Heckman2
78
Wandt3
105
Disease
Acute Myeloid
Leukaemia
(median age in
years:
51;
extremes 16
76)
Acute leukaemia
Acute myeloid
leukaemia
Gmur4
102
Acute leukaemia
GilFernandez5
190
Bone
marrow
transplantation
Intervention/measure
of
outcome
Transfusion parameter < 10 x
109/l vs < 20 x 109/l
primary
frequency
severe
bleeds
Result
Transfusion parameter
109/l vs < 20 x 109/l
Bleeding episode
Number
of
transfusions
Transfusion parameter
109/l vs = 20 x 109/l
Bleeding episode
Number
of
transfusions
No difference in number of
bleeding episodes
Higher use of transfusions
in < 20 x 109/l group
A2
No relationship between
severe
bleeding
and
platelet count
Fewer
platelet
transfusions in < 10 x 109/l
group
31 bleeding episodes in
1.9 % of 5 x 109/l group
0.07 % of 10 x 109/l group
No difference between 10
or 20 x 109/l groups
Fewer
platelet
transfusions
< 10 x
platelet
= 10 x
platelet
Transfusion parameter = 5 x
109/l vs = 10 x 109/l vs = 20 x
109/l
*both groups had higher risk
profile
Comparison of transfusion
regime with respect to severe
bleedings
Number
of
platelet
transfusions
No difference in severe
bleeds
21.5 % lower transfusion
requirement
Evidence
class
A2
Conclusions 6.4.2.2
In randomised studies usually performed in patients with standard risk
there was no difference in bleeding complications at a platelet transfusion
trigger of 10 x 109/L versus 20 or 30 x 109/L. However, the studies were too
Level 2
small to conclude that the various triggers are equal.
B
Level 3
230
Nevo 2007
Level 4
In clinical situations that can promote bleeding (sepsis, fever, high blast
count, extensive endothelial damage) consensus guidelines advise
increasing the platelet transfusion trigger to 20 x 10 9/L. This is not
supported by research.
D
Level 3
There are indications that patients who have experienced severe bleeding
in the preceding 5 days are at increased risk of recurrent bleeding.
C
Other considerations
In patients with an indication for anti-coagulant therapy and administration of anti-thymocyte
globulin (ATG), there was consensus in the Netherlands that the platelet transfusion trigger
should be increased to 40 x 10 9/L for the first 2 days of ATG treatment. (CBO Blood
Transfusion Guideline 2004). The working group deems that the number of platelet triggers
should be reduced (namely 10, 20, 50 and 100 x 10 9/L), as there is very little evidence
supporting the various triggers. Therefore, the current consensus recommends 50 x 10 9/L
for patients with an indication for anti-coagulant therapy. A trigger of 20 x 109/L is
recommended during administration of anti-thymocyte globulin (ATG).
Although the platelet count does not appear to be related to an increased risk of recurrent
bleeding in patients who have experienced severe bleeding in the preceeding 5 days, most
experts still feel that for the present it is safer to increase the platelet transfusion trigger to
20 x 109/L for such patients.
Recommendations 6.4.2.2
1.
2.
3.
4.
231
Use of the higher dose resulted in a significantly longer interval to the next transfusion and a
higher post-transfusion value. However, no difference was observed in occurrence of
bleeding (Cid 2007). Since then, two randomised studies have been performed with bleeding
as end point. A Canadian study was halted prematurely due to more WHO grade 4 bleeds
(5.2% versus 0%) in the low dose arm (Heddle 2009). The American PLADO (PLatelet
transfusion And DOsis) study in which a low, standard and high dose were compared in
more than 1200 patients was recently completed and showed no difference in bleeding (>
60% WHO grade 2 bleeds irrespective of dose) between the 3 arms (Slichter 2009).
Conclusions 6.4.2.3
For prophylactic transfusion of platelets, the use of a dose > 3 x 10 11
significantly increased the interval to the next transfusion and resulted in
higher post-transfusion values compared to a dose < 3 x 10 11. However, no
Level 1
difference was seen in the occurrence of bleeding.
A1
Level 2
Cid 2007
The PLatelet transfusion And DOsis (PLADO) study on more than 1200
patients showed no difference in bleeding between low, standard and high
doses, with > 60% WHO grade 2 bleeds in all 3 arms.
A2
Slichter 2009
Recommendation 6.4.2.3
A dose of approximately 3.5 x 1011 (this is the dose of a standard preparation and contains 5
x 109 platelets/kg for a patient of 70 kg) is recommended for prophylactic platelet
transfusions in adults.
6.4.2.4 Platelet transfusion policy for the prevention of bleeding in (elective)
procedures
The bleeding incidence is not known for most of the procedures that are frequently
performed on patients with thrombocytopenia. Certain rules of thumb are provided based on
empirical data and consensus. Use of the bleeding time to determine the indication for
platelet transfusions during procedures is unreliable (Lind 1991). Thorough preparation for
the procedure, checking for medications that interfere with haemostasis, monitoring the level
of clotting factors, discontinuing anti-coagulant medication if necessary and avoiding
hypothermia of the patient are advised (Bain 2004, Valeri 2007). Various studies have
examined bleeding during procedures.
Bone marrow aspiration
The ASCO and BCSH guidelines advise performing a bone marrow aspiration without
correction of haemostasis (ASCO 2001, BCSH 2003). A survey in the UK found a
complication frequency due to bleeding of 0.1% for bone marrow aspiration/biopsy, caused
by thrombocytopenia and/or an INR that was too high (Eikelboom 2005).
232
233
Recommendation 6.4.2.4
The following table can be used as a rule of thumb for platelet target values to
prevent bleeding during common, elective procedures.
Table 6.4.2 Target values for platelets during procedures
PROCEDURE
Platelets x 10 /L
Arthrocentesis
Ascites / pleural puncture (thin needle)
Ascites drain, pleural drain and pericardial drain
Bone marrow aspiration
Bone marrow biopsy (Jamshidi needle)
Blind organ biopsy or puncture
Bronchoscopy with biopsy or brush
Insertion of central venous catheter
Removal of central venous catheter
Small intestine biopsy
EMG
Endoscopy + deep loop biopsy or
polypectomy large polyp
Endoscopy without biopsy
Endoscopy with ordinary biopsy
ERCP with papillotomy
Eye surgery (except cataract)
Laparoscopy without biopsy
Laparoscopy with biopsy or procedure
Laser coagulation (not retina)
Liver biopsy (percutaneous)
Lumbar puncture
Myelography, saccography
Neurosurgery
Pacemaker implantation
Percutaneous Transhepatic Cholangiography
Plexus anaesthesia, epidural
Seldinger arterial
Muscle biopsy
Sclerosing oesophageal varices
Tooth/molar extractions
Thoracoscopy/arthroscopy
>50
N/A
>50
N/A
N/A
>50
>50
>50
N/A
>50
>20
>50
>20
>50
>50
>100
>50
>50
N/A
>50
>20*
>50
>100
>50
>50
>50
>50
>50
>50
>50
>50
234
Conclusions 6.4.2.5
With bleeding WHO grade 3, the aim is usually to increase the platelet
count to > 50 x 109/L.
Level 4
D
Level 4
For bleeding in vital organs such as the brain, nervous system and the eye,
experts usually advise to aim for a platelet count of > 100 x 10 9/L. Further
transfusion above this level is not deemed useful.
D
Recommendations 6.4.2.5
1.
2.
In the case of a severe bleed ( WHO grade 3), platelets should be transfused until
the bleeding stops and/or the platelet count is > 50 x 109/L.
With respect to bleeding in enclosed spaces of vital organs such as the brain, the
nervous system and the eye the advice is to transfuse platelets to a platelet count
of >100 x 109/L.
235
applies when there is not enough time to wait for the effect of a therapeutic dose of IVIG.
High doses (3 7 therapeutic units corresponding to 15 35 donor units) in combination
with IVIG resulted in a (temporary) improvement of the platelet count to > 50 x 10 9/L and
halted the bleeding (Salama 2008, Spahn 2008).
Conclusions 6.4.3.1
Platelet transfusions for the prevention of spontaneous bleeding are not
indicated in the case of auto-immune thrombocytopaenic purpura (ITP).
Level 4
D
Level 3
Recommendations 6.4.3.1
1.
2.
3.
4.
5.
Prophylactic platelet transfusions for the prevention of spontaneous bleeding are not
indicated in auto-immune thrombocytopaenic purpura (ITP).
For elective procedures in auto-immune thrombocytopaenic purpura (ITP) patients,
the recommended treatment is prednisolone or intravenous immunoglobulin (IVIG),
alone or in combination with platelet transfusions if necessary.
With auto-immune thrombocytopaenic purpura (ITP), platelets should preferably be
administered after intravenous immunoglobulin (IVIG).
In patients with auto-immune thrombocytopaenic purpura (ITP) and severe WHO
grade > 2 bleeding, (high dose) platelet transfusions are recommended and this is
also the case if it is not possible to wait for the effect of a therapeutic dose of
intravenous immunoglobulin (IVIG).
See also table 6.7. Indications and contra-indications for platelet transfusions in
thrombocytopenia caused by consumption and/or breakdown disorders (TTP, HUS,
HELLP, DIC, ITP, PTP and HIT(T)(T)).
236
Conclusion 6.4.3.2
In the case of severe bleeding in post-transfusion purpura (PTP) patients,
refractory after intravenous immunoglobulin (IVIG), severe bleeding could
Level 3
be halted with HPA-compatible platelet transfusions.
C
Win 1995
Recommendations 6.4.3.2
1.
2.
3.
4.
237
Conclusions 6.4.4.2
Cerebral infarctions have been described after platelet transfusions in
patients with thrombotic thrombocytopaenic purpura (TTP).
Level 3
C
Level 3
Swisher 2009
Recommendations 6.4.4.2
1.
2.
3.
6.4.4.3 Prevention of bleeding during procedures in patients with thrombotic microangiopathy (TMA)
Platelet transfusions are not recommended during simple procedures such as the insertion
of a central venous catheter (CVC) in patients with thrombotic thrombocytopaenic purpura
(TTP), particularly if treatment with plasma has not been started yet. This is because it may
promote thrombotic complications (Swisher 2009, Harkness 1981; Lind 1987; Bell 1991;
Kennedy 2000). No thrombotic complications of platelet transfusions have been described
for classic haemolytic uraemic syndrome (HUS) or disseminated intravascular coagulation
(DIC), but it remains to be seen whether these transfusions are effective. Elective
procedures should be postponed as long as possible, until treatment of the underlying
disease has started.
In the case of haemolysis elevated liver enzymes and low platelets (HELLP) syndrome and
in the rare case of HUS before delivery, platelet transfusions are given to prevent or treat
blood loss during delivery. In the case of HELLP, it is essential to terminate the pregnancy in
order to stop the disease. Non-evidence based guidelines advise to aim for > 50 x 109/L
platelets for a Caesarian section and > 20 x 10 9/L for a vaginal delivery (Van Dam 1989,
Sibai 1990, Sibai 2004, Baxter 2004, Haram 2009). Platelet transfusions have no therapeutic
effect on the disease. Corticosteroids (particularly antenatally administered dexamethasone)
improve the platelet count more quickly, without affecting the clinical outcomes for mother
and child (Woudstra 2010).
238
Conclusions 6.4.4.3
There are indications that for haemolytic uraemic syndrome (HUS) and
haemolysis ,elevated liver enzymes and low platelets (HELLP) syndrome,
a platelet count of > 50 x 109/L can be considered safe for a Caesarian
Level 3
section and a platelet count of > 20 x 109/L can be considered safe for a
vaginal delivery.
C
Level 2
Sibai 1990, Van Dam 1989, Sibai 2004, Baxter 2004, Haram 2009
There are indications that women with HELLP syndrome have a faster
post-partum recovery of the platelet count after (antenatal) administration
of corticosteroids. In the absence of clear gain on clinical outcomes,
corticosteroids are not recommended as a matter of routine.
A2
Other considerations
Platelet transfusions are not recommended for simple procedures in the case of thrombotic
thrombocytopaenic purpura (TTP), unless there is a strongly increased risk of bleeding as is
the case in extreme obesity or severe thrombocytopenia of < 5 x 10 9/L.
Whether a vaginal delivery is aimed for or not, one should always consider that an indication
for a Caesarian section may arise, it is therefore recommended to keep the platelet count
during childbirth > 50 x 109/L (the recommended platelet count for a Caesarian section).
According to the Dutch guidelines, this platelet count is also suitable for the use of epidural
analgesia. The same target value (> 50 x 10 9/L) can also be adhered to for other
procedures.
Recommendations 6.4.4.3
1.
2.
3.
For relatively simple procedures such as the insertion of a central venous catheter
(CVC) in the case of thrombotic thrombocytopaenic purpura (TTP), platelet
transfusions are not recommended unless there is a strongly increased risk of
bleeding, as is the case in severe obesity and severe thrombocytopenia < 5 x 109/L.
If it is decided to give platelet transfusions, the recommendation is to start preferably
with the administration of plasma.
In use and/or breakdown disorders other than thrombotic thrombocytopaenic purpura
(TTP), platelet transfusions are recommended for the prevention of bleeding during
emergency procedures or vaginal delivery and Caesarian section in order to achieve
a platelet count of > 20 x 109/L or > 50 x 109/L respectively.
See also table 6.4.4. Indications and contra-indications for platelet transfusions in
thrombocytopenia caused by consumption and/or breakdown disorders (TTP, HUS,
HELLP, DIC, ITP, PTP and HIT(T)).
239
severe internal bleeding was described in more than 50% of the patients, possibly due to
anti-coagulant therapy that was too aggressively titrated (Wester 2004). Risk factors for
bleeding with HIT(T) were analysed in a series of 269 patients, who were treated with the
anti-coagulant Argatroban. Severe bleeding occurred in 7.1% of the patients (Warkentin
2004). In addition to thrombosis and other factors, a prolonged (> 90 seconds) activated
partial thromboplastin time (aPTT) is an important risk factor for bleeding (Keeling 2006,
Hursting 2008).
In the case of HIT(T), expert reviews usually advise not to administer platelet transfusions
due to the risk of thrombosis (Warkentin 2004, Keeling 2006). However, confirmed cases of
thrombosis have not been described, whilst there have been case reports in which bleeding
(in 4 patients) was stopped after platelet transfusion without thrombotic events (Hopkins
2008).
Conclusions 6.4.4.4
Experts advise not to give platelet transfusions in the case of heparin
induced thrombocytopenia (and thrombosis) (HIT(T)) because of the risk of
Level 4
thrombosis.
D
Level 3
Hopkins 2008
Recommendations 6.4.4.4
1.
2.
Procedures
TTP
Contra-indication
HUS
HELLP
No indication
No indication
If there is an
increased
risk,
preferably after
starting plasma
therapy
Consider
Childbirth > 20
240
Grade >
bleeding
Consider
Indication
Indication
50 x 109/L
Consider
Indication
DIC
No indication
ITP
No indication
Consider (+ IVIG
or prednisolone)
Indication (+
IVIG)
PTP
Contra-indication
Contra-indication
HIT(T)
No indication
Consider
provided
(alternative ) anticoagulants
HPA
matched
Provided
(alternative)
anticoagulants
Other considerations
With normal spleen size, approximately 1/3 of the platelets are withdrawn from circulation. In
the case of splenomegaly depending on size and cause this part can increase to 90%.
With a normal bone marrow reserve, the platelet count can drop to approximately 60 x 109/L
in the case of splenomegaly.
In the case of an enlarged spleen, the platelet dose should be increased in order to achieve
the desired increment or to stop bleeding.
Recommendation 6.4.5
For patients with thrombocytopenia due to splenomegaly, higher dosages of platelet
transfusions are essential for the prevention and treatment of bleeding. Depending on the
size of the spleen, 2 4 times the standard dose should be administered for a therapeutic
transfusion.
6.4.6 Acquired thrombocytopathy
In various conditions such as uraemia, hyperviscosity due to para-proteinaemia, liver
cirrhosis and myelodysplasia acquired platelet function disorders can result in an
increased risk of bleeding. As a general rule, prophylactic platelet transfusions are not
indicated, unless there is also thrombocytopenia. Anticipation of any bleeding during
procedures and treatment of manifest bleeding is essential.
241
Uraemia
In 75% of patients with uraemic thrombocytopathy, the bleeding time is corrected after
administration of Desmopressin. This effect starts immediately and reaches a maximum after
4 hours (Manucci 1983). The effect is exhaustible and the interval between 2 doses should
be at least 24 hours. . Uraemia may be treated with dialysis. Platelet transfusions are rarely
necessary.
Para-proteinaemia
Hyperviscosity with para-proteinaemia can result in inhibition of platelet adhesion and/or
aggregation, resulting in prolongation of the bleeding time. This also applies to transfused
platelets. Treatment consists of plasmapheresis.
The para-protein can also have antibody activity against specific clotting factors. One
example is acquired von Willebrand Disease (vWD) due to autoantibodies against von
Willebrand Factor (vWF) in monoclonal gammopathy of undetermined significance
(MGUS) (Rinder 1997). Plasmapheresis is a category I (proven efficacy) indication for
hyperviscosity syndrome according to the criteria of the American Society For Apheresis
(ASFA) (ASFA 2010).
Liver cirrhosis
In addition to thrombocytopenia due to splenomegaly and a shortage of thrombopoietin,
thrombocytopathy may occur in liver cirrhosis (Roberts 2009). Platelet transfusions are not
administered for the prevention of spontaneous bleeding. A trigger of > 50 x 10 9/L is usually
maintained for procedures (BSCH 2003), although the role of (plasma and) platelet
transfusions for liver biopsy or insertion of a central venous line remains controversial (Bravo
2001, BCSH 2004, Lisman 2010).
Myelodysplasias (MDS)
In the case of Myelodysplasia (MDS), thrombocytopathy can occur in addition to
thrombocytopenia, caused by acquired von Willebrand Disease (vWD), function
abnormalities of the collagen receptor and/or autoantibodies (Rinder 1997). As is the case
with congenital thrombocytopathies, Desmopressin is the treatment of choice for the
correction of a bleeding tendency (Manucci 1997).
Conclusions 6.4.6
In thrombocytopathy caused by uraemia, Desmopressin corrects the
bleeding time in approximately 75% of the patients, with a maximum effect
Level 3
after 4 hours.
B
Level 3
242
Mannucci 1983
ASFA 2010
Level 3
Level 3
Manucci 1997
Other considerations
The effect of Desmopressin has not been examined in thrombocytopenia < 50 x 10 9/L and .
is not authorised for use in pregnancy or with suspected cerebral haemorrhage.
Desmopressin is also contra-indicated in cardiac decompensation. Cerebral and cardiac
infarction have been described as complications in renal patients. It is useful to determine
the bleeding time to monitor the effect of Desmopressin.
Recommendations 6.4.6
1.
In the case of acquired thrombocytopathy, the patient may be treated depending on
the cause and the severity of the bleeding or the nature of the scheduled procedure.
2.
For thrombocytopenia < 50 x 109/L and thrombocytopathy, platelet transfusions are
advised for procedures and bleeding and before administration of Desmopressin.
3.
Plasmapheresis is recommended for thrombocytopathic bleeding with hyperviscosity
syndrome caused by a para-protein.
4.
One should take into consideration that the effect of Desmopressin becomes
exhausted after a procedure and that a second dose should therefore be
administered after 24 hours.
243
in animal studies using Aspirin (Peter 2002). It is controversial in the case of a cerebral
haemorrhage in patients using platelet inhibitors whether platelet transfusions can reduce
the extent of the cerebral haemorrhage (Creutzfeldt 2009, Sansing 2009, Naidech 2009).
This question is being studied in the Netherlands (PATCH study).
Dipyrimadole
In general, it is not necessary to stop using Dipyrimadole before procedures.
Clopidogrel
Clopidogrel (Plavix) in combination with Aspirin is frequently administered after PTCA
and/or stent placement. This component inhibits platelet aggregation at the level of the
megakaryocyte and affects platelet function for up to 5 7 days. Clopidogrel is not thought
to affect transfused platelets (Quin 1999, Bennett 2001). The guideline on neuraxis blockade
and anti-coagulants states that the risk of neuraxis blockade with the use of clopidogrel is
barely increased, provided no other anticoagulant medication is used and there is no history
of bleeding (NVA 2004). A meta-analysis in cardiac surgery patients using Clopidogrel and
Aspirin with an indication for emergency surgery concluded that this was associated with
more bleeding, more transfusions , more post-operative complications and an increased
number of re-thoracotomies (Despotis 2008). A dose-dependent inhibition of platelet
aggregation was found in volunteers using a combination of Plavix and Ascal. Higher doses
of donor platelets (2 3 platelet transfusions, 10 15 donor units) were needed for
correction of the in vitro platelet aggregation (using mixing tests) when using Clopidogrel
(Vilahur 2006). This is not supported by clinical research.
IIb/IIIa inhibitors/Abciximab
Abciximab (Reopro)/Eptifibatide and Tirofiban hydrochloride a human Fab fragment from
chimeric monoclonal antibodies block the IIb/IIIa receptor and function as fibrinogen
receptor antagonist. Severe thrombocytopenia of < 20 x 10 9/L within 24 hours occurs in 0.2
1% of patients receiving Abciximab for the first time and more often with repeat
administration. This is caused by antibodies against platelets with Abciximab on their surface
(Curtis 2002). After stopping the medication, the platelet count increases by > 20 x 10 9/L/per
day. Platelet transfusions are only given in the case of severe bleeding and emergency
procedures and have a limited result (Curtis 2002). The guideline on neuraxis blockade and
anti-coagulants states that every form of neuraxis blockade is contra-indicated with IIb/IIIa
inhibitors (NVA 2004).
In acute surgery in patients on Abciximab, (large numbers of) platelet transfusions are
administered before . surgery in order to absorb the antibodies. Desmopressin is thought to
increase the absorption and may reduce the number of required platelet transfusions (Reiter
2005). The latter has not been clinically proven.
Other considerations
Anti-platelet agents are often used. . There has only been limited clinical experience on the
effect of platelet transfusions in the case of bleeding or invasive interventions.. .Usually it
involved patient-dependent, multi-disciplinary treatment advice that was determined by the
absolute indication for anti-platelet agents (recent cerebral infarction, unstable anginous
symptoms, recent stent) and the risk of bleeding during an intervention (in enclosed spaces
of vital organs such as the brain and eye) or biopsy in a parenchymatous organ, in which it is
244
hard to stop the bleeding.. We have provided only a general overview of the indications for
platelet transfusions with respect to the use of anti-platelet agents. Please refer to Chapter 8
for blood-saving measures in the peri-operative situation. For recommendations on regional
analgesia, please consult the Guideline on neuraxis blockade and anti-coagulants (NVA
2004).
Conclusions 6.4.6
It has been demonstrated that the use of acetyl salicylic acid (Aspirin)
and/or Clopidogrel in cardiac surgery patients with an indication for
emergency surgery is associated with more bleeding, more transfusions
Level 1
and more post-operative complications and re-thoracotomies.
A1
Level 3
It is likely that the use of acetyl salicylic acid does not result in (life
threatening) major blood loss during most procedures. For procedures in
enclosed spaces in which even slight bleeding can have disastrous
consequences, such as brain surgery the use of aspirin should be halted
5 10 days before the procedure.
C
Level 3
Fijnheer 2003
Level 3
Despotis 2008
Reiter 2005
245
Recommendations 6.4.6
1.
2.
3.
4.
5.
6.
6.5
If there are indications not to stop the use of acetyl salicylic acid (Aspirin) and
Clopidogrel before a cardiovascular procedure, one should take into account that
increased blood loss can occur.
In the case of procedures in non-critical locations, the use of Aspirin does not need to
be halted before the procedure.
For elective surgery in critical (enclosed space: brain, eye, inner ear, etc.) locations,
the use of Aspirin should be halted at least 5 days before the procedure.
For emergency procedures or bleeding under Aspirin therapy, a standard dose
platelet transfusion should be sufficient; at least 2 doses are necessary in the case of
combined use with Clopidogrel.
Research is necessary to determine the benefit of platelet transfusions in (cerebral)
haemorrhage during the use of platelet inhibitors.
Platelet transfusions alone or in combination with Desmopressin are necessary in
the case of an acute intervention with the use of anti-IIb/IIIa inhibitors in order to
absorb the antibodies.
Platelet transfusions in practice
246
of transfusion failure, but occur frequently in combination with HLA antibodies (Schnaidt
2000). The removal of leukocytes from platelet components has significantly reduced HLA
immunisation (> 80% reduction in primary immunisation and 40% reduction in secondary
booster immunisation) (TRAP 1997, Novotny 1995, Sintnicolaas 1995). Despite this, HLA
antibodies still occur in approximately 20% of recipients, but these antibodies do not always
result in transfusion failure. (Novotny 1995, TRAP 1997). Approximately 5% of patients
usually with strong multi-specific HLA antibodies exhibit transfusion refractoriness. After
previous pregnancies, women have an increased risk of forming HLA antibodies and platelet
refractoriness. (Novotny 1995, Sintnicolaas 1995). Leukocyte depletion of erythrocyte
components does not prevent HLA immunisation (Van de Watering 2003).
The presence of HLA and/or HPA antibodies can be demonstrated using screening tests,
usually ELISA based. HLA reference laboratories determine the specificity of HLA antibodies
and for the purposes of donor selection the HLA antigens against which antibodies are
not present. If the 1-hour CCI is insufficient despite HLA and ABO compatible transfusions, it
is useful to look for HPA specific antibodies using a sensitive test in a reference laboratory
(the Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA)).
6.5.1.3 Selection of HLA (HPA) compatible donors
Sanquin Blood Supply has a large HLA (partially HPA) typed database of voluntary donors
and a selection programme to select available donors for an immunised patient. The donor
must be called up for platelet apheresis and the blood must then be tested for transmissible
infections. Sometimes there are only a few suitable donors and donors with acceptable
mismatches are selected. The 1-hour yield for these transfusions is essential in determining
whether subsequent transfusions with the same mismatch are useful.
Conclusions 6.5.1
Several analyses have shown that platelet transfusion failure
(refractoriness) is caused by clinical factors such as fever, sepsis,
medication, extent of endothelial damage in the majority of cases, and
Level 2
only a minority of cases have an immunological cause.
B
Level 3
TRAP 1997
Novotny 1995
247
Level 2
Other considerations
As the logistics of HLA (and possibly HPA) matched platelet transfusions are complicated,
good clinical follow-up is very important for the further policy concerning donor selection.
Good communication between treating doctor, hospital transfusion service and the Clinical
Consultative Service of the Blood Supplier is essential for effective implementation and
support of HLA and/or HPA immunised patients.
Recommendations 6.5.1
1.
2.
3.
248
Level 3
Level 2
Level 2
Pihusch 2005
249
Leebeek 2008
Salama 2009, Kristensen 1997, Pihush 2005
Other considerations
Recombinant factor VIIa (rFVIIa) is used in practice in multi-therapy resistant life threatening
bleeding with thrombocytopenia. It is highly desirable for this to occur in a study context.
Recommendations 6.5.3.1
1.
For patients with thrombocytopenia and bleeding who cannot be, or are poorly,
corrected with platelet transfusions, it is recommended to consider increasing the
haematocrit to > 0.30 L/L in order to reduce the tendency to bleed.
2.
In patients with thrombocytopenia and mucous membrane bleeding (bleeding from
nose and gums, menorrhagia), anti-fibrinolytic medication can be considered to
reduce the tendency to bleed. Fibrinolysis inhibition is contra-indicated in
haematuria because of the risk of thrombus formation in the urinary tract.
3.
It is recommended that a (preferably national) registration takes place of the use of
recombinant factor VIaI (rFVIIa) for bleeding in patients with thrombocytopenia and
that protocols be developed for evaluation and reporting of the effect of the use of
rFVIIa for this indication.
6.5.3.2 Intravenous immunoglobulin (IVIG)
In a small randomised study in 12 patients with HLA antibodies, the administration of random
platelets resulted in only a temporary increased recovery (better 1-hour Corrected Count
Increment (CCI) and no difference in 24-hour CCI) after administration of intravenous
immunoglobulin (IVIG). (Kickler 1990). In the case of HLA antibodies, high dose IVIG
resulted in a varying effect on the count after incompatible platelet transfusions. There may
also have been autoantibodies or HPA antibodies present (Zeigler 1987, Kekomaki 1984,
Schiffer 1984, Knupp 1985, Siemons 1987).
Conclusions 6.5.3.2
In patients with HLA antibodies, high dose intravenous immunoglobulin
(IVIG) resulted in a favourable effect or no improvement of the count . after
incompatible platelet transfusions.
Level 3
C
Schiffer 1984; Zeigler 1987; Kekomaki 1984; Knupp 1985; Siemons
1987
250
Level 2
There are indications that for patients with HLA antibodies the
administration of random platelets results in only a temporary increase in
recovery (better 24-hour Corrected Count Increment (CCI), no difference in
-hour CCI) after administration of intravenous immunoglobulin (IVIG).
A2
Kickler 1990
Other considerations
Intravenous immunoglobulin (IVIG) is a very expensive treatment, which is used in posttransfusion failure due to demonstrated or suspected alloantibodies. The success described
in certain cases may be due to the simultaneous presence of autoantibodies or antibodies
against Human Platelet Antigens (HPA). The working group deems the positive result of
IVIG with HLA antibodies (the most frequent cause of immunological transfusion failure) as
insufficient evidence to justify this treatment.
Recommendation 6.5.3.2
Administration of intravenous immunoglobulin (IVIG) before a platelet transfusion is not
recommended in the case of refractoriness due to HLA antibodies.
6.6
Recommendations 6.6.1
Indications for plasma: see 2.2.3
6.6.2 Plasma transfusions in neonates
251
The haemostasis in neonates is insufficiently developed. The level of certain clotting factors
(FXII, FXI, prekallikrein (Fletcher factor) and high molecular weight (HMW) kininogen) in full
term neonates is 40 50% of the level in adults. In premature infants this is only 30 40%.
The vitamin K dependent factors (FII, FVII, FIX, FX) show similar percentages, as do the
anti-coagulation factors anti-thrombin and proteins C and S. Apart from rare, isolated
deficiencies (for example factor V .), plasma is administered to neonates primarily in
exchange transfusions (see Chapter 2 and 4.4.6.2.1), during surgical procedures (see
Chapter 5) and to full term and premature neonates in the case of bleeding and severely
prolonged coagulation times. There is no evidence to support prophylactic plasma
transfusions to premature infants with the aim of preventing cerebral haemorrhage (NNN
1996).
Conclusion 6.6.2
Level 4
252
Conclusions 6.6.3
Level 2
Level 3
Level 3
Loirat 1988
Loirat 2001, Ariceta 2009
Recommendations 6.6.3
1.
2.
3.
253
for atypical (dneg) HUS (Amorosi 1966, Bell 1991, Norris 2010, Ariceta 2009). The effect of
plasmapheresis in the case of HELLP is not clear, as this disease generally improves
spontaneously within 3 days after birth (Egerman 1999, Magann 1999, Egerman 1999).
Favourable results have been described for plasmapheresis in HELLP syndrome that
persists for > 72 hours post-partum or that occurred or deteriorated post-partum. (Martin
1990, Eser 2005). Randomised studies have not been performed. TTP can also occur during
. pregnancy or post-partum and is also an indication for plasmapheresis .. The same applies
to post-partum HUS (Egermann 1999b).
Two randomised studies of TTP showed improved results following plasmapheresis when
compared to plasma transfusion (Rock 1991, Henon 1991). A retrospective study of a small
patient group had previously demonstrated no difference between plasmapheresis and
plasma transfusion (Novitsky 1994).
Choice of plasma component or product
In a non-randomised, sequential study, the group treated with cryo-supernatant plasma
(CSP) had a better survival than the group treated with Fresh Frozen Plasma (plasma)
(13/18 versus 9/19) (Owens 1995). In a group of 18 patients who had not responded to
plasma exchange after 7 days, a good response was achieved 7 days after CSP in 61% and
82% were still alive after one month. In contrast, 67% of patients treated with plasma were
still alive after one month (Rock 1996). However, these studies were not continued.( CSP is
not a standard component in the Netherlands, but can be supplied by Sanquin Blood Service
with a doctors declaration).
Successful use of plasma treated with solvent and detergent (SD plasma) has been
described in several patients with therapy-resistant TTP (Moake 1994, Harrison 1996). No
difference was found in a small series that compared SD plasma to Fresh Frozen Plasma
(plasma) (Horowitz 1998). In a somewhat larger cohort study, SD plasma was as effective as
cryo-supernatant plasma (Scully 2007), but the study was not large enough to be certain that
the use of SD plasma did not require more plasmapheresis and/or a larger plasma volume.
The same applies to a randomised study with pathogen-inactivated (amotosalen/UVA)
plasma (Mintz 2006). A retrospective study,.from Spain, suggested that plasma treated with
methylene blue is probably inferior to plasma, both in achieving complete remission of TTP
and the volume required to achieve remission (Rio-Garma 2008, Alvarez-Larran 2004).
Systematic reviews by Brunskill and Michael concluded that more research is necessary
before conclusions can be drawn on the efficacy and adverse effects of the various plasma
components and components (Brunskill 2007, Michael 2009).
Conclusions 6.6.4.1
Plasma is the therapy of choice for all primary forms of thrombotic
thrombocytopaenic purpura (TTP) and atypical (d neg) HUS.
Level 2
B
Level 3
254
Amorosi 1966, Bell 1991, Norris 2010, Ariceta 2009, ASFA 2010
Doubt has been cast over treatment with plasma for Haemolysis Elevated
Liver enzymes and Low Platelets (HELLP), as the disease generally
improves spontaneously within three days . after birth.
Level 3
Level 3
(TTP),
Level 1
A2
B
Level 3
There are indications that complete remission is achieved less often with
methylene blue treated plasma and that more volume is required than is
the case with standard plasma to achieve complete remission with
thrombotic thrombocytopaenic purpura (TTP).
C
Other considerations
The working group is not convinced by the favourable results described for cryo-supernatant
plasma compared to standard plasma (FFP). No randomised research is available
concerning the choice between the various plasma components; Q-FFP, CSP and SD
plasma contain similar amounts of ADAMTS-13 (Scot 2007 Michael 2009).
Recommendations 6.6.4.1
1.
Treatment of Haemolysis Elevated Liver enzymes and Low Platelets (HELLP)
syndrome with plasma(pheresis) is not recommended, unless there has been either
no improvement or deterioration has occurred > 72 hours post-partum.
2.
Plasma administration is recommended as therapy of choice for thrombotic
thrombocytopaenic purpura (TTP) and for atypical (dneg) haemolytic uraemic
syndrome (HUS).
3.
Plasma administration / plasmapheresis is
indicated for thrombotic
thrombocytopaenic purpura (TTP) and HUS before or shortly after childbirth.
255
4.
5.
with malignancies;
256
257
Level 3
Level 3
258
Level 3
Level 3
Kaplan 2000
Level 3
There are indications that the use of plasma results in improved survival
compared to historical patients not treated with plasma for adults with
haemolytic uraemic syndrome (d+ HUS) as a complication of infections
with verotoxin producing E. coli.
C
Level 3
Dundas 1999
Recommendations 6.6.4.2
1.
2.
3.
4.
5.
6.
7.
259
pulmonary bleeding with Goodpastures syndrome and Wegeners Myeloma, the level of
clotting factors and fibrinogen should be checked before or during . plasmapheresis. It is
advisable to administer plasma (15 30 mL/kg based on coagulation screening) at the end
of plasmapheresis (Kaplan 1999).
Tapering oral anti-coagulants
With an INR > 7, vitamin K is given orally without bleeding and intravenously in the case of
bleeding. Pro-thrombin complex (4 factor concentrate) is given in the case of severe
bleeding.
Tapering fibrinolytics
It is recommended to administer tranexamic acid and repeat it after six hours if necessary.
Plasma (or fibrinogen concentrate) should be administered based on the aPTT and the
fibrinogen level if the activated partial thromboplastin time (aPTT) is prolonged and the
fibrinogen level is decreased. This can be repeated if necessary (Van Aken 1991).
Conclusions 6.6.4.3
Dilution coagulopathy can occur with daily plasmapheresis treatment (or
every other day) if plasma is not used as substitution liquid.
Level 3
C
Level 3
Kaplan 1999
Recommendations 6.6.4.3
1.
2.
3.
In the framework of this guideline, only the role of plasma for patients with severe DIC who
are bleeding will be described.
The use of plasma in patients with DIC who are bleeding has not been examined in a RCT.
In the many reviews on DIC, the recommendations are based on theoretical considerations
and expert opinions. There are few indications that the supplementation of clotting factors
enhances the process of DIC (Levi 2009). Sometimes large quantities of plasma are
necessary to supplement the clotting factors. In American literature, cryo-precipitate is often
administered, but this is not available in the Netherlands and fibrinogen concentrate is an
option for the reduction of the amount of plasma required (10 15 mL plasma/kg body
weight is required for a 0.5 g increase in fibrinogen). The efficacy and safety of recombinant
factor VIIa (rFVIIa) has not been demonstrated (Levi 2009).
Conclusions 6.6.4.4
In the case of severe disseminated intravascular coagulation (DIC) with
bleeding, the use of fibrinogen concentrate can reduce the plasma
Level 4
requirement.
D
Levi 2009
Recommendation 6.6.4.4
In patients with disseminated intravascular coagulation (DIC) who are bleeding, need to
undergo an invasive procedure or have some other severe risk of bleeding, treatment with
plasma, supplemented by a fibrinogen concentrate if necessary, should be considered.
6.6.5 Plasma component choice and blood group incompatibility
6.6.5.1 Plasma component choice
Various types of plasma components are available. In the Netherlands, we use quarantined
fresh frozen plasma (FFP), obtained exclusively from male non-transfused donors since
2007. If this guideline refers to plasma, it is referring to this component. In neighbouring
countries, methylene blue treated plasma (MB-FFP) is used and in a study context
photodynamically inactivated plasma is used, also obtained from individual donors.
Solvent-detergent treated (SD) plasma is a pooled plasma component and has fewer allergic
side effects compared to plasma from individual donors, including Transfusion Related Acute
Lung Injury (TRALI). A disadvantage is that not all pathogens are inactivated by SD
treatment, for example vCJD. The use of a specific prion-removal filtration step during the
preparation process of SD plasma is promising but has not yet resulted in an authorised
component.
The choice of plasma component depends strongly on the indication and whether a small
amount of plasma is required or massive amounts as in the case of TTP or DIC, in which SD
plasma has some benefits. There is hardly any research available to make evidence-based
choices in relation to the indication (Bianco 1999).
Conclusions 6.6.5.1
Experts are of the opinion that the choice of plasma component depends
Level 4
strongly on the indication and whether a small quantity of plasma is
261
Level 4
Bianco 1999
Bianco 1999
3.
4.
262
Akker ESA van den, de Haan TR, Lopriore E, Brand A< Kanhai HHH, Oepkes D. Severe fetal
thrombocvtopenia in Rhesus D alloimmunized pregnancies 2009.
Andrew M, Vegh P, Caco C, Kirpalani H, Jefferies A, Ohlsson A et al. A randomized,
controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr
1993;123:285-91.
Bednarek FJ, BeanS, Barnard MR, Frelinger AL, Michelson AD. The platelet hyporeactivity of
extremely low birth weight neonates is age-dependent . Thrombosis research 2009;124: 42-5.
Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory MR et al. Platelet
transfusion practices among neonatologists in the United States and Canada: results of a
survey. Pediatrics 2009;123:278-85.
5.
6.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Akker ESA van den, Oepkes D, Brand A, Kanhai HHH. Non-invasive antenatal management
of fetal and neonatal alloimmune thrombocytopenia: safe and effective. BJOG 2007;114: 46973.
Allan D, Verjee S, Rees S,Murphy MF, Roberts, DJ. Platelet transfusion in neonatal
alloimmune thrombocytopenia. Blood 2007; 109: 388-89.
Berkowitz RL, Kolb EA, McFarland JG ea. Parallel randomized trials of risk-based therapy for
fetal alloimmune thrombocytopenia. Obstet Gynecol 2006; 107: 91-96
Birchall JE, Murphy MF, Kaplan C, Kroll H: European collaborative study of the antenatal
management of feto-maternal alloimmune thrombocytopenia. Br J Hematol 2003;122:275
288.
Bussel JB, Richard MD, Berkowitz L, et al: Antenatal treatment of neonatal alloimmune
thrombocytopenia. N Engl J Med 1988;319.
Ghevaert C, Campbell K, Walton J ea. Management and outcome of 200 cases of
fetomaternal alloimmune thrombocytopenia. Transfusion 2007; 47: 901-10.
Jaegtvik S, Husebekk A, Aune B, et al: Neonatal alloimmune thrombocytopenia due to antiHPA1a antibodies; the level of maternal antibodies predicts the severity of thrombocytopenia
in the newborn. BJOG 2000;107:691694.
Kamphuis BJOG 2010.
Kiefel V, Bassler D, Kroll H, Giers G, Ditomasso J, Alber H ea.Antigen-positieve platelet
transfusion in neonatal alloimmune thrombocytopenia (NAIT). Blood 2006: 107: 3761-3
Management of alloimmune thrombocytopenia. International Forum Vox Sanguinis 2007; 93:
370-85.
Mueller-Eckhardt C, Kiefel V, Grubert A ea. 348 cases of suspected neonatal alloimmune
thrombocytopenia. Lancet 1989;1: 363-6.
Porcelijn L, Kanhai HHH: Diagnosis and management of fetal platelet disorders. In Rodeck
CH, WHIT(T)tle MJ (eds): Fetal Medicine: Basic Science and Clinical Practice. London,
Churchill Livingstone, 1999, pp 805815.
Radder CM, Brand A, Kanhai HH: A less invasive treatment strategy to prevent intracranial
hemorrhage in fetal and neonatal alloimmune thrombocytopenia.Am J Obstet Gynecol 2001;
185:683688.
Radder CM, Brand A, Kanhai HHH: Will it ever be possible to balance the risk of intracranial
haemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment
strategies to prevent it? Vox Sang 2003;84:318325.
Spencer JA, Burrows RF: Feto-maternal alloimmune thrombocytopenia: A literature review
and statistical analysis. Aust N Z J Obstet Gynecol 2001;41:4555.
Symington A, Paes B. Fetal and neonatal alloimmune thrombocytopenia : harvesting the
evidence to develop a clinical approach to management. Am J Perinatology 2010;
DOI/10.1055
Te Pas AB, Lopriore E, van den Akker ES, Oepkes D, Kanhai HH, Brand A, Walther FJ.
Postnatal management of fetal and neonatal alloimmune thrombocytopenia the the role of
matched platelet transfusion and IVIG. European Journal of Pediatrics 2007 ;166:1057-63
Von dem Borne AEGK, Decary I: ICSI / ISBT working party on platelet serology.
Nomenclature of platelet-specific antigens. Vox Sang 1990;58:176.
Williamson LM, Hacket G, Rennie J, et al: The natural history of fetomaternal
alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as was determined by
antenatal screening. Blood 1998;92:22802287.
263
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal
thrombocytopenia. N Engl J Med 1993;329: 1463-66.
Burrows RF, Kelton JG. Thrombocytopenia during pregnancy . In Greer JA, Turple AGG,
Forbes CD (eds) Hemostasis and thrombosis in Obstetrics and Gynecology. London,
Chapman & Hall 1992.
Christiaens GCML, Nieuwenhuis HK, Bussel JB ea. Comparison of platelet counts in first and
second newborns of women with immune thrombocytopenic purpura. Obstet Gynecol 1997;
90: 546-52.
Cook RL, Miller R, Katz VL, Cefalo RC. Immune thrombocytopenic purpura in pregnancy : A
reappraisal of management.Obstet Gynecol 1991; 78: 578-83.
Garmel SH, Graigo SD, Morin LM ea. The role of percutaneous blood sampling in the
management of immune thrombocytopenic purpura. Prenat Diagn 1995; 15: 439-45.
George JN, Woolf SH, Raskob GE ea. Idiopathic thrombocytopenic purpura: a practie
guideline developed by explicit methods for the American Society of Hematology. Blood
1996;88: 3-40.
George JN, Woolf SH, Raskob GE ea. Idiopathic thrombocytopenic purpura: a guideline for
diagnosis and management of children and adults. American Society of Hematology. Ann Int
Med 1998;30: 38-44.
Gernsheimer T , McGrae KR . Immune thrombocytopenic purpura in pregnancy. Curr Opin
Hematol 2007;14: 574-580.
Kaplan C, Daffos F, Forestier F ea. Fetl platelet counts in thrombocytopenic pregnancy.
Lancet 1990; 336: 979-82.
Letsky EA, Greaves M. Guidelines on the investigation and management of thrombocytopenia
in pregnancy and neonatal alloimmune thrombocytopenia. Maternal and neonatal
haemostasis and thrombosis Task force of the British Society for Haematology. Br J
Haematol 1996; 95: 21-6.
Marti-Carvajal AJ, Pena-Marti GE,Comunian-Carrasco G. Medical treatments for idiopathic
thrombocytopenic purpura during pregnancy Cochrane review 2009;4.
Payne SD, Resnik R, Moore TR ea. Maternal characteristics and risk of severe neonatal
thrombocytopenia and intracranial hemorrhage in pregnancies complicated by autoimmune
thrombocytopenia. Am J Obstet Gynecol 1997; 717: 149-55.
Samuels P, Bussel JB, Braitman IE ea. Estimation of thrombocytopenia in the offspring of
pregnant women with presumed immune thrombocytopenia. N Engl J Med 1990;323: 229-35.
Valat AS, Caulier MT, Devos P ea. Relationships between severe neonatal thrombocytopenia
and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia.
Br J Haematol 1998;103: 397-401.
Webert KE, Mittal R, Sigouin C,Heddle NM, Kelton JG. A retrospective 11-year analysis of
obstetric patients with idiopathic thrombocytopenic purpura. Blood 2003 ; 102: 4306-11.
2.
Bolton-Maggs PH, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ, et al. A review
of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO.
Br J Haematol 2006 Dec;135(5):603-33.
Almeida AM,Khair K, Hann I, Liesner R. Use of recombinant factor VIIa in children with inherited
platelet function disorders. B J Haematol 2003; 121: 477-81
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
BCSH 2004: Gibson BE,ea. Transfusion guidelines for neonates and older children Br J
Haematol 2004;124: 433-53
2.
3.
Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeiro RC, Rubnitz JE, et al. Traumatic
lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic
leukemia. Blood 2000 Nov 15;96(10):3381-4.
Howard SC, Gajjar AJ, Cheng C, Kritchevsky SB, Somes GW, Harrison PL, et al. Risk factors
for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia.
JAMA 2002 Oct 23;288(16):2001-7.
Howard SC, Gajjar A, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, et al. Safety of
lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. JAMA
2000 Nov 1;284(17):2222-4.
265
4.
5.
6.
7.
ASCO 2001 Schiffer CA Platelet transfusions in cancer. J Clin Oncol 2001; 19: 1519-38
van Veen JJ , Vora AJ, Welch JC. Lumbar puncture in thrombocytopenic children.
(correspondence) Br J Haematol 2004;127: 230-9
Norol F, Bierling P, Roudot-Thoraval F, Le Coeur FF, Rieux C, Lavaux A et al. Platelet
transfusion: a dose-response study. Blood 1998;92:1448-53.
Roy AJ, Jaffe N, Djerassi I. Prophylactic platelet transfusions in children with acute leukemia:
a dose response study. Transfusion 1973;13:283-90.
Literature 6.4.1
1.
2.
3.
4.
5.
6.
Almeida HJ, Lages B, Hoffmann T, Turritto V. Correction of the platelet adhesion defect in storage pool deficiency at elevated hematocrit-possible role of adenosine diphosphate. Blood
1996;87: 4214-22.
Bolton-Maggs PH, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ et al. A
review of inherited platelet disorders with guidelines for their management on behalf of the
UKHCDO. Br J Haematol 2006;135:603-33.
Fujimori K. Antepartum diagnosis of fetal intracranial hemorrhage due to maternal Bernard
Soulier syndrome. Obstet Gynecol 1999;94: 817-9.
Mannucci PM. Treatment of Willebrands disease B J Haematol 1997; 242 : 129-132.
Weiss HJ, Lages B, Hoffmann T, Turrito VT. Correction of the platelet adhesion defect in storage pool deficiency at elevated hematocrit-possible role of adenosine diphosphate.Blood
1996;10: 4214-22.
Manco-Johnson 2001.
Literature 6.4.2.1
1.
Stanworth SJ, Hyde C, Heddle N, Rebulla P, Brunskill S, Murphy MF. Cochrane database of
systematic reviews 2004
Literature 6.4.2.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
266
ASCO Platelet transfusion in cancer. CA Schiffer ea J Clin Oncol 2001 ;19: 1519-38.
BCSH: Guidelines to the use of platelet transfusions. Br J Haematol 2003;122:10-23.
Callow CR, Swindell R, Randall W, Chopra R. The frequency of bleeding complications in
patients with haematological malignancy following introduction of a stringent prophylactic
platelet transfusion policy. Br J Haematol 2002; 118: 677-82.
Dietrich B, Remberger M, Shanwell A, Svahn B-M, Ringden O. A prospective randomisezed
trial of a prophylactic platelet transfusion trigger of 10 x 109/l versus 30 x 109/l in allogeneic
hematopoietic progenitor cell transplantation recipients. Transfusion 2005; 45: 1064-72.
Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and
hemorrhage in patients with acute leukemia N.Eng J Med 1962; 266: 905-9.
Gil-Fernandez JJ, Alegre A, Fernandez-Villalta MJ, Pinilla I, Gomez Garcia V, Martinez C ea.
Clinical results of a stringent policy on prophylactic platelet transfusion: non-randomized
omparative analysis in 190 bone marrow transplant patients from a single institution. BMT
1995; 18: 931-5.
Gmur J, Burger J, Schanz U ea. Safety of a stringent prophylactic platelet transfusion policy
for patients with acute leukaemia Lancet 1991;338: 1223-6.
Heckman KD, Weiner GJ, Davis CS, Strauss RG, Jones MP, Burns CP. Randomised study of
prophylactic platelet transfusion treshold during induction therapy for adult acute leukemia:
10.000 l vs 20.000 l. J of Clinical Oncol 1997; 15: 1143-49.
Kerkhoffs JL, Eikenboom JC, van de Watering LWG, van Wordragen-Vlaswinkel RJ,
Wijermans PW, Brand A. The clinical impact of platelet refractoriness : correlation with
beeding and survivl. Transfusion 2008; 48: 1959-65.
Kerkhoffs JL, van Putten LJ, Novotny VMJ ea. Clinical effectivenedd of leuko-reduced ,
pooled donor platelet concentrates , stored in plasma or additive solutions with and without
pathogen reduction . Br J Haematol 2010.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Lawrence JB, Yomtovian RA, Hammons T ea. Lowering the prophylactic platelet transfusion
treshold: a prospective analysis. Leuk Lymphoma 2001; 41: 67-76.
Navarro JT, Hernandez JA, Ribera JM, ea. Prophylactic platelet transfusion treshold during
therapy for adult myeloid leukemia: 10.000/ microL. versus 20.000/microL. Haematologica
1998;83: 998-1000.
Nevo S, Fuller AK, Hartley E, Borinsky ME, Vogelsang GB. Acute bleeding complications in
patients after hematopoietic stem cell transplantation with prophylactic platelet transfusion
triggers of 10 x 10(9) and 20 x 10(9) per L. Transfusion 2007a; 47: 801-12.
Nevo S, Fuller AK, Zahurak ML, Hartley E, Borinsky ME, Vogelsang GB. Profound
thrombocytopenia and survival of hematopoietic stem cell transplant patients without clinically
significant bleeding, using prophylactic platelet transfusion triggers of 10 x 109 or 20 x 109
per L. Transfusion 2007b; 47: 1700-09.
Rebulla P, Finazzi G, Marangoni F, Avvisati G, Gugliotta L, Tognoni G ea. The treshold for
prophylactic platelet transfusions in adults with acute myeloid leukemia. N Engl J Med 1997;
337: 1870-5.
Sagmeister M, Oer L, Gmr J. A restrictive platelet transfusion policy allowing long-term
support of outpatients with severe aplastic anemia. Blood 1999; 93: 3124-6.
Slichter SJ & Harker . Thrombocytopenia: Mechanisms and management of defects in platelet
productionClin Haematol 1978;7:532.
Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, Gernsheimer
TB, Ness PM, Brecher ME, Josephson CD, Konkle BA, Woodson RD, Ortel TL, Hillyer CD,
Skerrett DL, McCrae KR, Sloan SR, Uhl L, George JN, Aquino VM, Manno CS, McFarland
JG, Hess JR, Leissinger C, Granger S. Dose of prophylactic platelet transfusions and
prevention of hemorrhage. N Engl J Med. 2009;362:600-13.
Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic
patients. Transfus Med Rev 2004; 18:153-67.
Stanworth SJ, Hyde C, Heddle N, Rebulla P, Brunskill S, Murphy MF. Cochrane database of
systematic reviews 2004.
Wandt H, Frank M, Ehninger G, Schneider C, Brack N, Daoud A ea. Safety and costeffectiveness of a 10 x 109/l trigger for prophylactic platelet transfusionscompared with the
traditional 20 x 109/l trigger: a prospective comparative trial in 105 patients with acute myeloid
leukemia. Blood 1998;91: 3601-6.
Zumberg MS, del Rosario ML, Nejame CF, Pollock BH, Carzarella L, Kao KJ ea. A
prospective randomised trial of prophylactic platelet transfusion and bleeding incidence in
haematopoietic stem cell transplant recipients: 10.000 vs 20.000 l trigger. Biology of Blood
Marrow Transplant 2002; 8: 569-76.
4.
5.
6.
7.
Cid J, Lozano M. Loer or higher dosis for prophylaxic platelet transfusions: results of a metaanalysis of randomized controlled trials. Transfusion 2007; 47: 464-70.
Goudnough LT, Kuter DJ, McCullough J ea. Prophylactic platelet transfusions from health
apheresis donors undergoing treatment with thrombopoietin. Blood 2001;98: 1346-51.
HeddleNM, Cook RJ, Tinmouth A, Kouroukis CT, Hervig T, Klapper E, Brandwein JM ea.A
randomized controlled trial comparing standard and low dose strategies for transfusion of
platelets (STOP) to patients with thrombocytopenia.Blood 2009;113: 1564-73.
Klumpp TR, Herman JH, Gaughan P ea. Clinical consequences of alterations in platelet
transfusion dose: a prospective , randomized, double blind trial. Transfusion 1999;39: 674-81
Norol Blood F, Bierling P, Roudotthoraval F ea. Platelet transfusion: a dose-response study
1998;92: 1448-53.
Sensebe L, Giraudeau B, Bardioaux L ea. The efficiency of transfusing high doses of platelets
in hematologic patients with thrombocytopenia: results of a prospective, randomized, open,
blinded end point (PROBE) study. Blood 2005;105: 862-4.
Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, Gernsheimer
TB, Ness PM, Brecher ME, Josephson CD, Konkle BA, Woodson RD, Ortel TL, Hillyer CD,
267
8.
Skerrett DL, McCrae KR, Sloan SR, Uhl L, George JN, Aquino VM, Manno CS, McFarland
JG, Hess JR, Leissinger C, Granger S. Dose of prophylactic platelet transfusions and
prevention of hemorrhage. N Engl J Med. 2009;362:600-13.
Tinmouth A, Tannock IF, Crump M ea. Low dose prophylactic platelet transfusions in
recipients of an autologous peripheral blood progenitor cell transplant and patients with acute
leukemia: a randomized controlled trial with a sequential Bayesian design. Transfusion 2004;
44: 1711-9.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Bain BJ. Bone marrow biopsy morbidity and mortality: 2002 data.Clin Lab Haematol 2004;26;:
315-8 [wordt nu niet in de tekst aangehaald.
Bosly A, Muylle L, Noens L, Pietersz R, Heims D, Hubner R et al. Guidelines for the
transfusion of platelets. Acta Clin Belg 2007;62:36-47.
Caturelli E, Squillante MM, Andriulli A, Siena DA, Cellerino C, de Luca F, Marzano MA,
Pompili M, Rapaccini. Fine-needle liver biopsy in patients with severe impaired coagulation.
Liver 1993;13:270-3.
Doerffler ME, Kaufman B, Goldenberg AS. Central venous catheter placement in patients with
disorders of hemostasis. Chest 1996;110: 185-8.
Eikelboom JW Bone marrow biopsy in thrombocytopenic or anticoagulated patients. Br J
Haematol 2005;129:562-3.
Grant A, Neuberger J. Guidelines on the use of liver biopsy in clinical practice: Brit Soc
Gastroenterol. Gut 1999;45: suppl 4:1-11.
Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991;77:2547-52.
McVay PA, Toy PTCY, Lack of increased bleeding after liver biopsy in patients with mild
hemostatic abnormalities . Am J Clin Pathol 1990; 94: 747-53.
Mumtaz H, Williams V, Hauer-Jensen M, Rowe M, Henry-Tilman RS, Heaton K, et al. Central
venous catheter placement in patients with disorders of hemostasis. Am J Surg
2000;180:503-6.
Ray CE, Shenoy SS. Patients with thrombocytopenia : outcome of radiological placement of
central venous access devices. Radiology 1997;204: 97-9.
Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M et al. Platelet
transfusion for patients with cancer: clinical practice guidelines of the American Society of
Clinical Oncology. J Clin Oncol 2001;19:1519-38.
Sharma P, McDonald GB, Banaji M. The risk of bleeding after percutaneous liver biopsy:
relation to the platelet count. J Clin Gastroenterol 1982;4:451-3.
Stecker MS, Johnson MS, Ying J, McLennan G, Agarwal DM, Namyslowski J, ea. Time to
hemostasis after traction removal of tunneled cuffed central venous catheters. J Vasc Interv
Radiol 2007; 18: 1232-9.
Tercan F, Ozkan U, Oguzkurt L. US-guided placement of central vein catheters in patients
with disorders of hemostasis. Eur J Radiol 2008;65: 253-6.
Valeri CR, Khuri S, Ragno G. Nonsurgical bleeding diathesis in anemic thrombocytopenic
patients : role of temperature, red blood cells, platelets and plasma-clotting proteins.
Transfusion 2007;47:206-8S).
ASCO Platelet transfusion in cancer. CA Schiffer ea J Clin Oncol 2001 ;19: 1519-38.
BCSH: Guidelines to the use of platelet transfusions. Br J Haematol 2003;122:10-23.
ASCO Platelet transfusion in cancer. CA Schiffer ea J Clin Oncol 2001 ;19: 1519-38.
BCSH: Guidelines to the use of platelet transfusions. Br J Haematol 2003;122:10-23.
Rebulla P. Platelet transfusion triggers in difficult patients. Transfus Clin Biol 2001;8: 249-54.
268
BCSH: Guidelines for the investigation and management of ITP in adults, children and
pregnancy Br J Haematol 2003; 120: 574-96.
2.
3.
4.
5.
McCrae KR, Herman JH. Post-transfusion purpura: two unusual cases and a literature review.
Am J Hematol 1996;52: 205-11.
Win N, Peterkin MA, Watson WH. The therapeutic value of HPA-1a negative platelets
transfusion in post-transfusion purpura complicated by life-threatening haemorrhage. Vox
Sang 1995: 69: 138-9.
3.
4.
5.
6.
7.
8.
9.
10.
Baxter JK, Weinstein L. HELLP syndrome : the state of the art. Obstet Gynecol Surv 2004;59:
838-45.
Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic
purpura-hemolytic syndrome: clinical experience in 108 patients . New Engl J Med 1991; 325:
398-403.
Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management
BMC Pregnancy and Childbirth 2009;9:1-15.
Harkness DR, Byrnes JJ, Lian E ea. Hazard of platelet transfusion in thrombotic
thrombocytopenis purpura. JAMA 1981;246: 1931.
Kennedy VA, Vesely SK, George JN. The potential risks of platelet transfusions in patienst
with thrombotic thrombocytopenic purpura-hemolytic syndrome (TTP-HUS. Blood 2000;96:
631 (abstract).
Lind SE. Thrombocytopenic purpura and platelet transfusion (letter) Ann Int Med 1987;106:
478.
Sibai BM. Diagnosis, controversies and management of hemolysis, elevated liver enzymes
and low platelet count.Obstet Gynecol 2004; 103: 981-91.
Sibai BM. The HELLP syndrome : much ado about nothing? Am J Obstet Gynecol 1990;162:
311-6.
Swisher KK, Terrell DR, Vesely SK, Kremer Hovinga J, Lammle B, George JN. Clinical
outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura.
Transfusion 2009;49: 873-87.
Van Dam PA, Renier M, Baekelandt M, Buytaert P, Uuttenbroeck Disseminated intravascular
coagulation and the syndrome of hemolysis , elevated liver enzymes and low platelets in
severe eclampsia . Obstetrics and Gynecology 1989;73: 97-102.
269
5.
6.
Wester JPJ, Haas FJLM, Biesma DH, Leusink JA, Veth G. Thrombosis and hemorrhage in
heparin-induced thrombocytopenia in seriously ill patients. Intensive Care Med 2004;30:192734.
Keeling D, Davidson S, Watson. The management of heparin-induced thrombocytopenia. Br J
Haematol 2006; 133:259-69.
3.
Bishop JF, Matthews JP, McGrath K, Yuen K, wolf MM, Szer J. Factors influencing 20-hour
increments after platelet transfusion Transfusion 1991; 31: 392-6.
Slichter SJ. Evidence-based Platelet Transfusion Guidelines. Hematology 2007; 172-80
Kerkhoffs JL, Eikenboom JC, van de Watering LWG, van Wordragen-Vlaswinkel RJ,
Wijermans PW, Brand A. The clinical impact of platelet refractoriness : correlation with
beeding and survivl. Transfusion 2008; 48: 1959-65
Literature 6.4.6
1.
2.
3.
4.
5.
6.
7.
8.
Literature 6.4.6
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
270
Creutzfeldt CJ, Weinstein JR, Longstreth WT, Becker KJ, McPharlin TO, Tirschwell DL. Prior
antiplatelet therapy, platelet transfusion threrapy, and ouycome after intracerabral bleeding.
Joornal of Stroke and Cerebrovascular Diseases 2009;18: 221-8.
Curtis BR, Swyers A,Divgi A ea. Thrombocytopenia after second exposure to abcicimab is
caused by antibodies that recognize abcicimab coated platelets. Blood 2002;99: 2054-9.
Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of
perioperative bleeding in cardiac surgery. Transfusion 2008;48:2S-30S.
Fijnheer R, Urbanus RT, Nieuwenhuis HK, Staken van gebruik van acetylsalicylzuur vr een
operatie meestal niet nodig. Ned Tijdschr Geneeskunde 2003; 147: 21-25.
Flordal PA Eur J Anaesthesiol Suppl 1997;14: 38-41.
Naidech AM, Jovanovic B, Liebling S, Garg RK,Bassin SL, Bendok BR, Bernstein RA, Alberts
MJ,Batjer HH. Reduced platelet activity is associated with early clot growth and worse 3month outcome after intracerebral hemorrhage. Stroke 2009;40: 2398-401.
Peter FW,Benkovic C, Muehlberger T, Vogt PM, Homann HH, Kuhnen C, Wiebalck A,
Steinau HU. Effects of desmopressin on thrombogenesis in aspirin-induced platelet
dysfunction. Br J Haematol 2002;117:658-63.
Reiter R, Jilma-Stohlawetz P, Horvath M, Jilma B. Additive effects between platelet
concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor
eptifibatide Transfusion2005;45:420-6.
Richtlijn Neuraxisblokkade en antistolling NVA 2004.
Sansing LH, Messe SR, Cucchiara BL, Cohen SN, Lyden PD, Kasner SE. Prior antiplatelet
use does not affect hemorrhage growth or outcome after ICH. Neurology 2009; 72: 1397-402.
Valeri CR, Giorgio A, Macgregor H, Ragno G. Circulation and distribution of autotransfused
fresh, liquid preserved and cropreserved baboon platelets. Vox Sang 2002;83:347-51.
Blood Transfusion Guideline, 2011
12.
13.
14.
Vilahur G, Choi BG, Zafar MU, Viles-Gonzalez JF, Vorchheimer DA Fuster V, Badimon J.
Normalization of platelet activity in clopidrogel-treated subjects (J Thrombosis Haemostasis
2006;5: 82-90.
Quinn MJ and Fidzgerald DJ.Ticlopedine and clopidrogel.Circulation 1999;100:1667-72
Bennett JS.Novel platelet inhibitors.Annual Redv Med 2001;52:161-84.
Literature 6.5
1.
2.
3.
4.
5.
6.
Legler TJ, Fischer I, Dittmann J, Simson G, Lynen R, Humpe A, et al. Frequency and causes
of refractoriness in multiply transfused patients. Ann Haematol 1997;74:185-9.
Novotny VM, Doorn R van, Witvliet MD, Claas FH, Brand A. Occurence of allogeneic HLA
and non-HLA antibodies after transfusion of prestorage filtered platelets and red blood cells: a
prospective study. Blood 1995;85:1736-41.
Schnaidt M, Wernet D.Platelet-specific antibodies in female blood donors after pregnancy.
Transfus Med 2000; 10: 77-80.
Sintnicolaas K, Marwijk-Kooij M van, Prooijen HC van, Dijk BA van, Putten WL van, Claas FH,
et al. Leukocyte depletion of random single donor platelet transfusions does not prevent
secondary human leukocyte antigenalloimmunization and refractoriness: a randomized
prospective study. Blood 1995;85:824-8.
The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and
ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet
transfusions. N Engl J Med 1997;337:1861-9.
Van de Watering L, Hermans J, Witvliet M, Versteegh M, Brand A. HLA and RBC
immunization after filtered and buffy-coat depleted blood transfusion in cardiac surgery: a
randomized controlled trial.Transfusion 2003;43:765-71.
4.
5.
6.
Brand A, Sintnicolaas K, Claas FH, Eernisse JG. ABH antibodies causing platelet transfusion
refractoriness. Transfusion 1986;26:463-6.
Heal JM, Rowe JM, McMican A, Masel D, Finke C, Blumberg N. The role of ABO matching in
platelet transfusions. Eur J Haematol 1993; 50: 110-7.
Julmy F, Ammann RA, Taleghani BM, Fontana S, Hirt A, Leibundgut K. Transfusion efficacy
of ABO major-mismatched platelets (PLTs) in children is inerior to that of ABO-identical PTLs.
Transfusion 2009; 49: 21-33.
Lee EJ, Schiffer CA. ABO compatibility can influence the results of platelet transfusion.
Results of a randomized trial. Transfusion 1989;29:384-9.
Ogasawara K, Ueki J, Takenaka M, Furihata K. Study on the expression of ABH antigens on
platelets. Blood 1993;82:993-9.
TRAP Slichter ea NEJM 1997.
5.
6.
7.
Aubuchon JP, Wildt-Eggen J de, Dumont LJ, for BEST, Reducing the variation in
performance of antibody titrations. Vox Sang 2008;95:57-65.
Cooling L. ABO and platelet transfusion therapy. Immunohematology 2007; 23: 20-33.
Fung MK, Downes KA, Shulman IA. Transfusion of platelets containing ABO incompatible
plasma: a survey of 3158 American laboratories. Arch Pathol Lab Med 2007;131: 909-16.
Harris SB, Josephson CD, Kost CB, Hillyer CD. Non-fatal intravascular hemolysis in a
pediatric patient after after transfusion of a platelet unit with high titer anti-A. Transfusion
2007; 47: 1412-7.
Heal JM, Rowe JM, McMican A, Masel D, Finke C, Blumberg N. The role of ABO matching in
platelet transfusions. Eur J Haematol 1993; 50: 110-7.
Mair B, Benson K, Transfusion 1998; 38: 51-52.
Larsson LG, Welsh VJ, Ladd DJ. Acute intravascular hemolysis secondary to out-of group
platelet transfusion Transfusion 2000; 40:9002-6.
271
8.
Valbonesi M, De Luigi MC, Lercari G, Florio G, Bruni R, Van Lint MT , Occhini D. Acute
intravascular hemolysis in two patients transfused with dry platelet units obtained from the
same ABO incompatible donor. Int J Artif Organs 2000; 23: 642-6.
Literature 6.5.2.3
1.
2.
3.
4.
5.
6.
Literature 6.5.2.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
Bartholomew JR, Salgia R, Bell WR. Control of bleeding in patients with immune and nonimmune thrombocytopenia with aminocaproic acid. Arch Intern Med 1989;149:1959.
Fernandez F, Goudable C, Sie P, Ton-That H, Durand D, Suc JM, et al. Low haematocrit and
prolonged bleeding time in uraemic patients: effect of red cell transfusions. Br J Haematol
1985;59:139-48.
Fricke W. Lack of efficacy of tranexamic acid in thrombocytopenic bleeding. Transfusion 1991
;31:345-8.
Garewal HS, Durie BGM. Antifibrinolytic therapy with amino caproic acid for the control of
bleeding in trombocytopenic patients. Scand J Haematol 1985;35:497.
Kristensen J, Killander A, Hippe E ea. Clinical experience with recombinant factor VIIa in
patients with thrombocytopenia. Haemostasis 1997 ; 26(suppl) : 159-164.
Leebeek FWG, Eikenboom HCJ. Recombinant factor VIIa : plaatsbepaling in de
hematologische praktijk. Ned Tijdschrift voor Hematologie 2008 ;5 : 166-74.
Livio M, Gotti E, Marchesi D, Mecca G, Remuzzi G, Gaetano G de. Uraemic bleeding: role of
anaemia and beneficial effect of red cell transfusions. Lancet 1982;2:1013-5.
Pihusch M, Bagigalupa A, Szer J, Von Depka M, Gaspar-Blaudschun B, Hyveled L, Brenner
B. Recombinant activated factor VII in the treatment of bleeding complications following
hematopoietic stem cell transplantation. J Thrombosis Haemostasis 2005 ;3 : 1935-44.
Salama A,Rieke M, Kiesewetter H, Depka M von. Experiences with recombinat FVIIa in the
emergency treatment of patients with autoimmune thrombocytopenia. Ann Hematol 2009 ;
88 : 11-15.
2.
3.
4.
272
5.
6.
Siemons L, Colpin G, Muylle L,Bock R de,Peetermans ME. Improved response of an Rhpositive patient with aplastic anemia to donor platelet transfusions with intravenous anti-D
Rhesus antibodies. N Engl J Med 1987;317: 1667-8.
Zeigler ZR, Shadduck RK, Rosenfield GS,Mangan KF, Winkelstein A, Oral A, Ramsey GE,
Duquesnoy RJ. High-dose intravenous gammaglobulin improves responses to single donor
platelets in patients refractory to platelet transfusion. Blood 1987;70:1433-6.
2.
3.
4.
Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma
clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;
126: 139-52.
Roback JD, Caldwell S, Carson J ea. Evidence-based practice guidelines for plasma
transfusion. Transfusion 2010;50: 1227-39.
Northern Neonatal Nursing Initiative (NNN) Trial Group. A randomized trial comparing the
effect of prophylactic intravenous fresh frozen plasma , gelatin or glucose on early mortality
and morbidity in preterm babies. Eur J Pediatr 1996;7: 580-8.
Aken WG van, Briet E, Dudok de Wit C, Kunst AJM, Meer J van der. Zijn er nog indicaties
voor het transfunderen van plasma? Ned Tijdschr Geneeskd 1991;135:1631-4.
Literature 6.6.2
1.
2.
3.
4.
5.
6
7
10
11
Barbot J, Costa E, Guerra M ea. Ten years of prophylactic treatment with fresh frozen plasma
in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result from
congenital deficiency of von Willebrand factor cleaving protease. Br J Haematol
2001;113:649-51.
Filler G, Radhakrishnan S, Strain L, Knoll G. Goodship TH. Challenges in the management of
infantile factor H associated hemolytic uremic syndrome. Pediatr Nephrol 2004; 19: 908-11.
Heuvelink AE, Loo DM te, Monnens LA. Hemolytisch uremisch syndroom op de kinderleeftijd.
Ned Tijdschr Geneeskd 2001;145:620-5.
Loirat C, Sonsino E, Hinglais N, Jais JP, Landais P, Fermanian J. Treatment of the childhood
haemolytic uraemic syndrome with plasma. A multicentre randomized controlled trial. The
French Society of Paediatric Nephrology. Pediatr Nephrol 1988;2:279-85.
Loirat C. [Post-diarrhea hemolytic-uremic syndrome: clinical aspects]. Arch Pediatr
2001;8(Suppl 4):S776-84.
Noris M, Remuzzi G . Atypical hemolytic-uremic syndrome..N Engl J Med. 2009
22;361(17):1676-87.
Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic thrombocytopenic
purpura related to severe ADAMTS13 deficiency in children.Pediatr Nephrol. 2009
Jan;24(1):19-29.
Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro
C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB; European Paediatric
Study Group for HUS. Guideline for the investigation and initial therapy of diarrhea-negative
hemolytic uremic syndrome.Pediatr Nephrol. 2009 ;24(4):687-96.
Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, Rizzoni G, Taylor CM,
Van de Kar N, Zimmerhackl LB; European Paediatric Research Group for HUS. A
classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and
related disorders.Kidney Int. 2006 70(3):423-31.
Stella CL, Dacus J, Guzman E, Dhillon P, Coppage K, How H, Sibai B. The diagnostic
dilemma of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the obstetric
triage and emergency department: lessons from 4 tertiary hospitals. Am J Obstet Gynecol.
2009 ;200(4):381.e1-6.
Fakhouri F, Roumenina L, Provot F, Salle M, Caillard S, Couzi L, Essig M, Ribes D, DragonDurey MA, Bridoux F, Rondeau E, Frmeaux-Bacchi V.Pregnancy associated hemolytic
273
uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol.
2010;21(5):859-67.
Literature 6.6.4
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
274
Alvarez-Larran A, Del Rio j, Ramirez C, ea. Methylene blue photoinactivated plasma vs fresh
frozen plasma as replacement fluid for plasma exchange in thrombotic thrombocytopenic
purpura. Vox Sang 2004; 86: 246-51
Amorosi EL, Ultmann JE. Thrombotic trombocytopenic purpura: report of 16 cases and review
of the literature. Medicine (Baltimore) 1966;45:139-59.
Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med
1991;325:398-403.
Brunskill SJ, Tusold A, Benjamin SJ, Murphy MF, A systematic review of randomized
controlled trials for plasma exchange in the treatment of thrombotic thrombocytopenic
purpura.Transfusion Medicine 2007; 17: 17-35
Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic
thrombocytopenic purpura. Blood 1977;50:413-7.
Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N
Engl J Med 1977;297:1386-9.
Egerman RS, Sibai BM. HELLP syndrome. Clin Obstet Gynecol 1999;42:381-9.
Egerman RS, Sibai BM. Imitators of preeclampsia and eclampsia. Clin Obstet Gynecol
1999;42:551-62.
Eldor A. Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy.
Best Pract Res Clin Haematol 1998;11:475-95.
Eser B, Guven M, Unal A, Coskun R,Altuntas F, Sungur M, Serin IS, Sari I, Cetin M. The role
of plasma exchange in HELLP syndrome. Clin Appl Thromb Hemost 2005; 11: 211-7
George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic
syndrome. Blood 2000;96:1223-9.
Harrison CN, Lawrie AS, Iqbal A, Hunter A, Machin SJ. Plasma exchange with
solvent/detergent-treated plasma of resistant thrombotic thrombocytopenic purpura. Br J
Haematol 1996;94:756-8.
Henon P. [Treatment of thrombotic thrombopenic purpura. Results of a multicenter
randomized clinical study]. Presse Med 1991;20:1761-7.
Horowitz MS, Pehta JC. SD Plasma in TTP and coagulation factor deficiencies for which no
concentrates are available. Vox Sang 1998;74(Suppl 1):231-5.
Magann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin
Obstet Gynecol 1999;42:532-50.
Martin JN, Files JC, Blake PG, Norman PH, Martin JW, Hess JW,Morrison JC, Wiser WL.
Plasma exchange for preeclampsia. Postpartum use for persistently severe preeclampsiaecclampsia with HELLP syndrome. Am J Obstet Gynecol 1990; 62: 126-137
Mintz PD, Neff A, Menotove JE ea. A randomized controlled phase III trial of therapeutic
plasma exchange with fresh frozen plasma prepared with with amotosalen and ultraviolet A
light compared to untreated FFP in thrombotic thrombocytopenic purpura. Transfusion
2006;46: 1693-1704
Moake J, Chintagumpala M, Turner N, McPherson P, Nolasco L, Steuber C, et al.
Solvent/detergent-treated plasma suppresses shear-induced platelet aggregation and
prevents episodes of thrombotic thrombocy topenic purpura. Blood 1994;84:490-7.
Novitzky N, Jacobs P, Rosenstrauch W. The treatment of thrombotic thrombocytopenic
purpura: plasma infusion or exchange? Br J Haematol 1994;87:317-20.
Owens MR, Sweeney JD, Tahhan RH, Fortkolt P. Influence of type of exchange fluid on
survival in therapeutic apheresis for thrombotic thrombocytopenic purpura. J Clin Apheresis
1995;10:178-82.
21.
22.
23.
24.
25.
26.
27.
Literature 6.6.4
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
275
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Literature 6.6.4.3
1.
2.
Literature 6.6.5.2
1.
2.
276
Bejamin RJ, Antin JH. ABO incompatible bone marrow transplantation: the transfusion of
incompatible plasma may exacerbate regimen-related toxicity Transfusion 1999;39: 1273-4.
Bianco C. Choice of human plasma preparations for transfusion. Transfus Med Rev
1999;13:84-8.
3.
Shanwell A, Anderson T M-L, Rostgaard K, Edgren G, Norda R, Nyren O ea. Posttransfusion mortality among recipients of ABO-compatible but non-identical plasma. Vox Sang
2009; 96: 316-23.
277
Set up
278
Hypotension:
Rule out acute haemolytic transfusion reactions (see point 3)
Consider bacterial contamination, sepsis (see point 3)
Consider anaphylactic reaction (see points 2 and 3)
Consider TRALI (see point 2)
Consider non-transfusion related cause
2.
Dyspnoea:
Rule out overfilling based on clinical symptoms. Monitor fluid balance. Chest
X-ray if indicated; if overfilling/TACO (Transfusion Associated Circulatory
Overload) is diagnosed, remove excess fluid and if the response is good,
consider slow administration of the component
Consider anaphylactic reaction (skin symptoms, glottis oedema), (see point 4)
If there is no anaphylactic reaction or overfilling, consider Transfusion Related
Acute Lung Injury (TRALI), chest X-ray
Fever:
2 C temperature increase and/or cold shivers: consider bacterial
contamination, take blood cultures (aerobic/anaerobic) from patient and
3.
279
4.
component; in the case of sepsis, treat as such and start antibiotics; consider
haemolytic transfusion reaction (see paragraph 7.2); all negative: see
paragraph 7.2. ((F)NHTR).
< 2 C increase without cold shivers: can this be explained by patients clinical
condition? (take note of temperature curve); has the patient used nonsteroidal anti-inflammatory drugs (NSAIDs) or other anti-pyretic medication
(paracetamol)?; If there are no indications for bacterial contamination or mix
up and haemolysis has been ruled out: give paracetamol if necessary and
consider resuming the transfusion if the patients temperature decreases and
he/she is in good condition.
Itching/urticaria:
If there are no anaphylactic symptoms (such as glottis oedema, hypotension,
shock): consider administering an anti-histamine. Transfusion can be
resumed with adequate response.
The recommendations provided below are based on the opinions of experts and
international guidelines (evidence level 4).
Recommendations 7.1.2
1.
A nurse must observe the patient for 5 to 10 minutes after starting the transfusion of
each new unit. The vital functions should be recorded at the end of this period.
Clearly define which parameters should be monitored (heart rate, temperature, blood
pressure, etc.) during transfusion and at what frequency..
2.
In the case of a (suspected) transfusion reaction other than itching or urticaria, the
transfusion should be stopped and the unit disconnected if necessary, in consultation
with the treating physician. The infusion system should be left in place. Rapid and
targeted examination by the blood transfusion laboratory is also required.
3.
The treating physician should be contacted for the differential diagnosis and
treatment of acute transfusion reactions. It is recommended that the treating
physician follows the above-mentioned algorithm (7.1) suspected acute transfusion
reaction (including explanation) or the hospitals own schedule that has been
adapted to the local situation. For more detailed recommendations for (suspected)
specific reactions: see paragraph 7.2.
4.
If anaphylactic symptoms (such as glottis oedema, hypotension, shock) are present:
disconnect the unit immediately, connect a neutral infusion solution (e.g. 0.9% NaCl)
and treat as an anaphylactic reaction: anti-histamines, corticosteroids and adrenalin,
if necessary. Consult the transfusion specialist about diagnosis of IgA deficiency. See
also paragraph 7.2.3.
5.
Before disconnecting the unit, it should first be sealed (clamped), in order to prevent
the reflux of blood from the patient to the donor unit.
6.
If the blood component is disconnected, it should be returned to the blood transfusion
laboratory as soon as possible for further examination. The hospital must provide
instructions for disconnection, transport & storage conditions, and the method of
sampling and these instructions must be followed.
7.
Reporting: Transfusion reactions must first be reported to the treating doctor and the
blood transfusion laboratory. Sanquin Blood Supply should be contacted as soon as
possible with each suspected transfusion reaction or incident that may have
280
8.
9.
10.
11.
7.2
consequences for other components from this donor (these donors) (for example:
suspected bacterial or viral contamination of a unit, suspected Transfusion Related
Acute Lung Injury (TRALI)) The haemovigilance official of the hospital reports all
reactions and incidents to the TRIP (Transfusion Reactions in Patients) National
Haemovigilance Office. Severe reactions or calamities must also be reported to the
Health Care Inspectorate (IGZ). See www.tripnet.nl for reporting and definitions of
severity.
The blood sample for compatibility testing (also called cross-match blood) must be
stored for seven days at a maximum of 4 C to 8 C for testing of possible transfusion
reactions.
Systematic training of nurses in the field of prevention, recognition and treatment of
transfusion reactions is indicated.
In addition to a haemovigilance official, each hospital should also have a
haemovigilance nurse/employee. An important task of the haemovigilance
nurse/employee is the training of all people involved in the prescription and
administration of blood components (see Chapter 9.3).
The working group is of the opinion that haemovigilance should encompass both
transfusions of (short shelf-life) blood components and blood-saving techniques.
Non-infectious complications of transfusions
The recommendations formulated in 7.2 are also largely based on level 4 evidence i.e.
expert opinions, international guidelines and manuals. If the evidence is stronger than level
4, this is indicated in the text.
7.2.1 Acute haemolytic transfusion reaction
An acute haemolytic transfusion reaction is defined as increased breakdown of erythrocytes
occurring within several minutes after the start to 24 hours after the end of a transfusion.
Symptoms can include: decrease in blood pressure 20 mmHg systolic and/or diastolic,
fever/cold shivers, nausea/vomiting, back pain, dark or red urine, no or only slight increase in
Hb or unexpected decrease in Hb.
Scientific support
An acute haemolytic transfusion reaction is usually the result of a transfusion involving (an)
ABO incompatible blood component(s) due to administrative errors (Rudmann 1995,
Mollison 1997, Sazama 1990, Linden 2000, SHOT 2008). The risk of a fatal reaction
occurring depends, among other factors, on the amount of transfused blood, the clinical
condition of the patient and the time lapsed between the start of the transfusion and the start
of the treatment (Rudmann 1995, Sazama 1990, SHOT 2008). Incompatible units of plasma
and platelet concentrates can also cause haemolysis due to antibodies and in rare cases
can cause an acute haemolytic transfusion reaction. Antibodies (both IgM and IgG) against
ABO antigens are very efficiently able to activate the complement system and thereby cause
severe haemolysis.
Other antibodies can also cause an acute haemolytic transfusion reaction. Activation of the
complement system causes the release of anaphylatoxins (C5a, C4a, C3a), serotonin and
histamine, which in turn cause some of the clinical symptoms associated with an acute
haemolytic transfusion reaction. Various mechanisms activate the clotting cascade and this
Blood Transfusion Guideline, 2011
281
Level 3
Acute haemolytic transfusion reactions are rare, but can be very severe
and are usually the result of administrative errors in the transfusion
procedure. The risk of a fatal reaction occurring depends, among other
factors, on the amount of transfused blood, the clinical condition of the
patient, and the time lapsed between the start of the transfusion and the
start of the treatment.
C
Level 3
282
intravascular
Recommendations 7.2.1
1.
2.
3.
4.
5.
6.
283
Level 3
Level 3
Redman 1996
Redman 1996
Issitt 1998
Other considerations
Knowledge of the patients erythrocyte antibody history is very important, both when
requesting a blood transfusion and when searching for a diagnosis of undefined transfusion
reactions and/or unexplained blood breakdown. This information should be directly
accessible for the entire life of the patient. The TRIX database for irregular red cell
antibodies is a national database in which confirmed irregular antibodies (see 3.3.3) can be
registered. It is of great importance that all hospitals are linked to this system, contribute to
the registration and consult this register prior to transfusion. Although a transfusion card
given to a patient if he/she has irregular antibodies is an aid, in practice this is not
conclusive.
Recommendations 7.2.2
1.
2.
3.
284
4.
285
transfusion of platelets or plasma, one could consider using components obtained from IgA
deficient donors (Sandler 1995, Council of Europe 2007).
Haptoglobin deficiency with anti-haptoglobin of IgG and IgE specificity was found in 2% of
Japanese patients who were examined after an anaphylactic transfusion reaction. Rare
cases of anaphylactic reactions have also been described in deficiencies of plasma factors,
such as complement and von Willebrand factor (Shimada 2002).
Conclusions 7.2.3
A cause is found in only a minority of anaphylactic transfusion reactions.
Antibodies against IgA are the most frequently described cause of
Level 3
anaphylactic reactions to (blood) components that contain plasma.
C
Level 4
Level 3
Shimada 2002
Recommendations 7.2.3
1.
2.
3.
4.
286
Level 3
Kluter 1999
Vamvakas 2007
287
Level 3
Level 3
The use of platelet concentrates in which 70% of the plasma has been
replaced by platets storage solution (PAS) appears to result in a reduction
of allergic transfusion reactions.
C
Other considerations
In most international guidelines, recommendations are made based on expert opinion
(evidence level 4) to administer an anti-histamine for other i.e. mild and non-anaphylactic
allergic reactions; usually the transfusion can then proceed with caution. After one (or more)
allergic reaction(s), an anti-histamine can be administered as pre-medication for future
transfusions.
Rare cases of clusters of allergic reactions have been observed, associated with certain
materials used in the processing of donor blood. The so-called red eye syndrome was
associated with allergic symptoms and conjunctivitis in recipients of erythrocytes that were
treated with a certain filter for the removal of leukocytes (Centers for disease control and
prevention 1998). It is important to recognise such a pattern in a timely manner, by reporting
this type of transfusion reaction.
Recommendations 7.2.4
1.
2.
3.
It is recommended to administer an anti-histamine in the case of a mild and nonanaphylactic allergic transfusion reaction; usually the transfusion can proceed with
caution.
After one (or more) mild and non-anaphylactic allergic transfusion reaction(s), an
anti-histamine can be administered as pre-medication for future transfusions.
For patients with mild and non-anaphylactic allergic transfusion reactions, the blood
components for administration do not need to undergo any extra processing steps,
such as washing.
7.2.5 (Febrile) non-haemolytic transfusion reaction ((F)NHTR) and mild nonhaemolytic febrile reaction
A non-haemolytic (also called febrile) transfusion reaction (NHTR) is defined as a
temperature increase 2 oC with or without cold shivers (CS) during or in the first two hours
after transfusion, with normalisation of the temperature within 24 hours after transfusion or
CS within this same period. During a non-haemolytic transfusion reaction, there are no other
relevant signs/symptoms and there are no indications for haemolysis, an infectious cause or
any other cause.
288
289
Heddle 2007
There is no sound evidence to support the standard administration of premedication to prevent febrile reactions during transfusions.
Level 3
C
B
Level 3
Level 3
Heddle 2007
Kennedy 2008
Kennedy 2008
Heddle 2007
Recommendations 7.2.5
1.
The diagnosis of non-haemolytic transfusion reaction (NHTR) is a diagnosis based
on exclusion.
2.
A non-haemolytic transfusion reaction (NHTR) is never life-threatening, but
transfusion reactions that are life-threatening such as acute haemolysis transfusion
reaction (AHTR), bacterial contamination and Transfusion Related Acute Lung Injury
(TRALI) must be ruled out before the diagnosis of NHTR may be made.
3.
When evaluating the cause of an increase in temperature during blood transfusion,
the patients entire clinical condition should be analysed, and a temperature curve
should be constructed.
4.
Anti-pyretic medication (paracetamol, NSAIDs) can be administered to combat the
symptoms of a non-haemolytic transfusion reaction (NHTR).
5.
The transfusion can be resumed once an acute haemolytic transfusion reaction
(AHTR), bacterial contamination and Transfusion Related Acute Lung Injury (TRALI)
have been ruled out.
7.2.6 Transfusion Related Acute Lung Injury (TRALI)
Transfusion Related Acute Lung Injury (TRALI) is a severe lung complication of plasmacontaining blood components (Palfi 2001). TRALI is associated with symptoms of acute lung
injury, such as dyspnoea and hypoxia, which occur during or within six hours after a
transfusion. The chest X-ray shows bilateral interstitial abnormalities.
Scientific support
290
TRALI is an adult respiratory distress syndrome (ARDS) or acute lung injury (ALI) that
occurs within six hours after a transfusion of blood components (TRIP definition: symptoms
of acute lung damage such as dyspnoea and hypoxia that occur during or within six
hours after a transfusion, with bilateral interstitial abnormalities on the chest X-ray,immunohaematological and bacteriological tests showing no abnormalities).
An international consensus meeting of the TRALI consensus panel in Canada in 2004 set
criteria to meet the definition of (TR)ALI. Other causes for dyspnoea or hypoxia (transfusionrelated or not) in particular volume overload should be ruled out. If there is a known risk
factor for ALI (e.g. sepsis, pneumonia, massive blood transfusion or the use of a heart-lung
machine), the Canadian consensus group suggests using the name possible TRALI.
(Kleinman 2004). According to the working group of the American National Heart, Lung and
Blood Institute, the diagnosis of TRALI can be made despite the presence of other ALI risk
factors if there is a strong time relationship (within six hours after start of transfusion) to the
transfusion (Kopko 2007, Goldman 2005).
Since 2005, approximately 20 reports of TRALI are made annually to TRIP that fall under the
above-mentioned definition. According to the literature, the mortality of TRALI (5 15%) is
lower than ALI due to other causes. In the period 2005 through 2007, TRIP received a total
of six reports of death following a TRALI (imputability possible, probable or certain). As is the
case in the United States and The United Kingdom, TRALI is therefore the most important
transfusion-related cause of death in the Netherlands (Goldman 2005, SHOT 2007, FDA
2008).
TRALI with an immunological cause (immune-mediated TRALI) is caused by incompatible
leukocyte antibodies.
Other biologically active substances in blood components can also activate leukocytes and
cause TRALI. Both causes can amplify each other (double hit) via a mechanism in which a
trigger is initially present in the endothelium of the lung vasculature. The transfusion then
supplies the second hit. According to some authors, immune-mediated TRALIs are
generally more severe than a TRALI for which no immunological cause has been
demonstrated (Bux 2005).
Since 2007, only plasma from male (never transfused) donors is used for fresh frozen
plasma in the Netherlands (due to the increased risk of the presence of HLA antibodies in
women as a result of pregnancy). In addition, only plasma from male donors is added to
combined platelet concentrates. It is expected that in the course of 2011, apheresis platelets
for use in paediatric situations will also be obtained exclusively from male donors.
It is estimated that this has resulted in the total number of TRALI reports decreasing by one
third (TRIP report 2010).
Conclusions 7.2.6
Adult Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI)
that occurs in a patient within six hours of the administration of plasmacontaining blood components is possibly a Transfusion Related Acute Lung
Level 3
Injury (TRALI).
C
Kleinman 2004
291
Level 3
Bux 2005
Other considerations
Although leukocyte serological testing is not essential to confirm the diagnosis of TRALI
(Kleinman 2004), the findings can support the donor policy (e.g. future donations from
involved donors). As . TRALI is a donor-linked reaction, the reaction should be reported both
to TRIP and to Sanquin Blood Supply and also to the Health Care Inspectorate if the
reaction is severity grade 2 or higher.
Recommendations 7.2.6
1.
A chest X-ray should be made for every suspected case of Transfusion Related
Acute Lung Injury (TRALI).
2.
(Possible) Transfusion Related Acute Lung Injury (TRALI) is a clinical diagnosis.
3.
Other causes of dyspnoea or hypoxia (transfusion-related or not) particularly
volume overload should be ruled out before making the diagnosis Transfusion
Related Acute Lung Injury (TRALI).
4.
Transfusion Related Acute Lung Injury (TRALI) must be reported both to TRIP and to
Sanquin Blood Supply.
5.
For each transfusion reaction that meets the definition of Transfusion Related Acute
Lung Injury (TRALI), the donor(s) and the patient (in the case of administration of a
leukocyte-containing blood component) must be examined for antibodies against
HLA and/or granulocytes. Sanquin Blood Supply will coordinate this testing.
292
Affsap 2007
Robillard 2008
Recommendations 7.2.7
1.
2.
3.
293
4.
294
Mortality in the acute phase (Kroll 1993, Taaning 1994) is in the order of magnitude of 5
8% and is primarily caused by cerebral haemorrhages. If these do not occur the patient
usually makes a full recovery. If a patient has experienced a period of PTP, there is a limited
chance of recurrence with subsequent blood transfusions. For this reason, if these patients
experience severe bleeding, it is advisable after a period of PTP to give platelets
obtained from donors who are negative for the antigen (usually HPA-1a) against which the
antibody is targeted (Kroll 1993).
Conclusions 7.2.8
Post-transfusion purpura (PTP) is a severe, potentially lethal adverse
effect, characterised by severe, transient thrombocytopenia with or
without bleeding that occurs an average of nine (spread 1 24) days
after a transfusion of cellular blood components in a patient with a history
Level 3
of pregnancy or transfusion. These are patients older than 15 years,
usually (> 85%) women.
C
Level 3
Level 3
McFarland 2001
Level 3
McFarland 2001
Kroll 1993
Other considerations
In surgical patients with thrombopenia who have had a transfusion, post-transfusion purpura
(PTP) should be included in the differential diagnosis along with suspected heparin-induced
thrombocytopenia (HIT).
Recommendations 7.2.8
1.
295
2.
3.
4.
5.
296
Level 4
AABB 2006, Hayakawa 1993, Ohta 1996, Williamson 2007, Raad van
Europa 2008
Other considerations
Following irradiation of cellular blood components with 25 Gy, the T-lymphocytes present in
these components are no longer able to divide and therefore no longer able to cause GvHD.
Recommendation 7.2.9
In order to prevent a transfusion-associated graft-versus-host reaction (TA-GVHD), Tlymphocyte containing blood components must be irradiated (25 Gy) before administration
to patients at-risk (see Chapter 2 for indications for irradiated blood components).
7.2.10 Secondary haemochromatosis (haemosiderosis)
Secondary haemochromatosis (haemosiderosis) is defined as iron accumulation,with a
ferritin level of at least 1000 g/L, with or without organ damage caused by frequent
erythrocyte transfusions.
Scientific support
Secondary haemochromatosis (haemosiderosis) is primarily the result of frequent blood
transfusions. (Malcovatti 2007, Modell 2000, Borgna-Pignatti 2005). One unit of erythrocyte
concentrate contains approximately 200 mg of iron, whilst no more than 1 2 mg of iron is
absorbed from the diet by the intestines on a daily basis (Andrews 1999). Symptoms of
haemochromatosis can occur after administration of approximately twenty erythrocyte
concentrates. Often, the ferritin level is higher than 1000 g/L. In general, it can be said that
organ damage due to iron accumulation with transfusions occurs more quickly than with
primary haemochromatosis (iron accumulation due to a congenital defect).
Iron accumulation can result in fibrosis and cirrhosis of the liver (Deugnier 2008), heart
failure and cardiac arrhythmias (Buja 1971), diabetes mellitus, hypothyroidism,
hypoparathyroidism and hypogonadism (Allen 2008). Disseminated pigmentation in the skin
may occur as a result of an increase in melanocytes.
The diagnosis of iron accumulation starts with the determination of the ferritin level in the
blood. As ferritin is an acute phase protein, it can also be elevated in the case of
inflammation and tissue damage without iron accumulation. Tests to determine organ
damage consist of laboratory tests for liver enzymes and -foetoprotein (with cirrhosis),
FSH, LH, testosterone, oestradiol, growth hormone, cortisol, prolactin, calcium, phosphate
and glucose. The organ damage can also be evaluated by means of an ECG, MRI or
297
ultrasound of the liver and/or heart and bone densitometry (Wood 2008). A liver biopsy can
be performed to determine the extent of iron accumulation and to demonstrate signs of
fibrosis or cirrhosis.
Iron chelation should be started (see Chapter 5) if the ferritin level is > 1000 g/L, or if more
than 20 erythrocyte concentrates have been administered, the patient remains transfusiondependent and the patients life expectancy is more than one year. In the Netherlands, there
are three authorised types of medication available for iron chelation: deferoxamine,
deferiprone and deferasirox. The aim of iron chelation therapy is to achieve a safe iron
concentration in the tissues and to neutralise free oxygen radicals. The aim is to achieve a
ferritin level < 1000 g/L and to normalise the MRI pattern of the liver. Deferoxamine is
generally the component of choice, due to the many years of experience with this
component and the mild side effects (Roberts 2005). Deferiprone should preferably be used
in the case of cardiac iron accumulation (Piga 2006).
Conclusions 7.2.10
Secondary haemochromatosis (haemosiderosis) is primarily the result of
frequent blood transfusions.
Level 3
C
Level 3
Level 1
Level 2
Roberts 2005
to secondary
the preferred
Piga 2006
Other considerations
Experts recommend deferasirox if the patient does not tolerate deferoxamine or deferiprone,
or in the case of poor therapy compliance resulting in insufficient iron chelation.
Recommendations 7.2.10
1.
298
2.
3.
4.
dependent and has a life expectancy of more than one year must be started on iron
chelation and the ferritin level in the blood must be monitored.
Iron chelation must be started in transfusion-dependent patients with a ferritin level >
1000 g/L and a life expectancy of more than one year.
The aim of iron chelation is to achieve a ferritin level < 1000 g/L and to normalise
the MRI pattern of the liver.
Deferoxamine is recommended as the component of choice. Deferiprone is
recommended in the case of cardiac iron accumulation, possibly in combination with
deferoxamine. Deferasirox is recommended if the patient does not tolerate either of
these iron chelators, or in the case of poor therapy compliance resulting in insufficient
iron chelation.
Level 3
299
Schnaidt 1996
Other considerations
Knowledge of the patients HLA and HPA antibody history is very important both when
requesting a platelet or granulocyte component for transfusion and when diagnosing a case
of undefined thrombocytopenia after transfusion. This information should be directly
accessible for the entire life of the patient, preferably in the TRIX database for irregular red
cell antibodies.
Recommendations 7.2.11
1.
2.
The patients antibody history including HLA and HPA antibodies should be
consulted with each request for a platelet or granulocyte component (see also
Chapters 3 and 6).
Data concerning the presence of HLA and/or HPA antibodies should be included in
the patients transfusion history.
300
1st author
Study design
Number
patients
Study arm
Jensen4
one centre
197
LD
full blood
14 vs 63% ?
7
Houbiers
multi-centre
697
LD
RBCwbc
36 vs 32%
Jensen8
one centre
586
LD
RBCwbc
11 vs 30% ?
Tartter9
one centre
221
LD
RBC+bc
16 vs 44% ?
10
Tittlestadt
one centre
279
LD
RBCwbc
38 vs 45% ?
Van Hilten11 multi-centre
560
LD
RBCwbc
22 vs 23%
LD = leukocyte-reduced by means of filtration; RBC = erythrocyte concentrate;
wbc = without buffy coat; +bc = with buffy coat;
?= analysis limited to transfused patients; analysis in randomisation groups
p < 0.05
n.s.
p < 0.05
p < 0.05
n.s.
n.s.
301
Opelz 1997), but also for heart (van der Mast 1997, Katz 1987), liver and combined kidneypancreas (Waanders 2008) transplantation. The larger studies still demonstrate a favourable
effect of transfusions (Terasaki 1995).
Conclusions 7.2.12
Leukocyte reduction for open heart surgery in which large amounts of
transfusions are given has a significantly favourable effect on the
prevention of post-operative infections.
Level 1
A2
A1
Level 2
Level 2
Bilgin 2004,
Vamvakas 2007
Amato 2008
Other considerations
The clinical significance of the changes in cellular immunity caused by blood transfusions is
unknown. Thanks to the current immuno-suppressants, the transplantation results are so
good that immune-modulating transfusions with the accompanying disadvantages (10
30% antibodies) are no longer worth the slight gain in transplant survival (Koneru 1997,
Alexander 1999).
Recommendations 7.2.12
1.
2.
7.3
302
for pooled platelet concentrates that are prepared from several donor units. Dutch research
(Sanquin Blood Supply Foundation 2001) confirms that in particular platelet suspensions,
which are stored at room temperature, are components at risk of bacterial contamination.
The risk has been decreased by changing the method of disinfection and by using the first
millilitres of blood donations to fill the test tubes (de Korte 2006). All platelet components are
cultured by Sanquin Blood Supply and only released if the culture has remained negative
until the time of release. Blood components that have been contaminated with bacteria can
result in transient bacteraemia in the recipient, but also in sepsis. Sometimes the symptoms
cannot be distinguished from a haemolytic transfusion reaction, namely fever, cold shivers,
tachycardia, changes in systolic blood pressure (both increase and decrease), nausea
and/or vomiting, shortness of breath, lower back pain, shock (Sanquin Blood Supply
Foundation 2001). Both the symptoms themselves and the time at which the bacterial
contamination manifests itself can vary greatly, which hampers the formation of a protocol.
In the Netherlands, approximately three transfusion reactions per year are probably or
definitely the result of a blood component contaminated by bacteria (de Korte 2006).
Infected components should be traced by means of a good haemovigilance system (de
Korte 2006, TRIP report 2008) and a report should be sent back to Sanquin Blood Supply
immediately.
TRIP distinguishes three reporting categories with respect to bacterial complications
(see www.tripnet.nl):
A.
Blood cultures must be collected from the patient and from the (remainder of the
already) transfused blood component , the bag being sealed and stored in the correct
manner, for a reliable diagnosis of a bacterial infection caused by blood components
.Instead of or in addition to blood cultures may also be taken from other blood
components prepared from the same donation. The strains detected in the patient
and the blood component should be identical. Genetic testing may be required,
depending on the type of bacteria.
B.
If symptoms are observed in a patient and a positive blood culture is found in the
patient, this is referred to as a post-transfusion bacteraemia/sepsis: defined by TRIP
as: the occurrence of clinical symptoms of bacteraemia/sepsis during, following or
some time after a blood transfusion, where a relevant positive blood culture is
obtained from the patient and with or without a causal link being made to an
administered blood component.
C.
303
Conclusions 7.3.1
Platelet suspensions in particular, which are stored at room temperature,
are components at risk of bacterial contamination.
Level 3
C
Level 3
De Korte 2006
TRIP rapport 2008
Other considerations
The limit for a febrile reaction and therefore also for a standard collection of a blood culture
has been set at an increase of 2 C and/or cold shivers. Two independent collections are
performed as standard procedure, in order to increase the chance of a positive blood culture.
In order to reduce the risk of contamination to a minimum, instructions for the collection of a
blood culture, the disconnection, transport and storage conditions and method of sampling of
a blood component must be present in the hospital and these instructions must be followed.
Recommendations 7.3.1
1.
2.
3.
4.
One bacterial culture from the component and two blood cultures from the patient
must be performed in case of a febrile reaction 2 C and/or cold shivers. For a
febrile reaction < 2 C, blood cultures should be taken depending on the doctors
clinical judgement.
The hospital must provide instructions for disconnection, transport & storage
conditions and the method of sampling, and these instructions must be followed.
Infected blood components should be traced by means of a good haemovigilance
system. (Suspected) cases of bacterial contamination of blood components should
be reported to Sanquin Blood Supply as soon as possible.
If a report of bacterial contamination of a blood component is sent to Sanquin Blood
Supply (or another manufacturer) and the blood component has already been
administered or is being administered at the time, it is essential to monitor the patient
for symptoms of bacteraemia/sepsis.
304
present in the blood, but cannot be detected yet by the tests that are used. In addition to
performing laboratory tests on donor blood, it is important to ask questions during the donor
anamnesis about increased risk, so that together with voluntary, non-paid donors this
guarantees the optimum safety of blood components .
The transmission of an infection can also be suspected if a blood transmissible viral infection
is detected in a transfused patient and there is no other obvious cause for this infection. If
there is a realistic suspicion, Sanquin Blood Supply will test the relevant donors. Conversely,
if a blood transmissible infection is found in a donor, doubt can be cast over the safety of
previous donations. Even if the stored samples from the previous donations are found to be
negative after additional testing, the relevant hospitals will be contacted in look-back
procedures. If relevant, the patient should undergo additional testing.
Conclusion 7.3.2
The risk of a viral infection as a result of transfusion of a blood component
(in the Netherlands) is very low.
Level 4
D
Recommendation 7.3.2
A realistic suspicion of a post-transfusion viral infection should be reported to Sanquin Blood
Supply immediately.
305
the previous policy of CMV tested blood following the implementation of leuko-reduction.
However, there is no evidence to support anti-CMV testing of leukocyte-reduced blood
(Preiksaitis 2000, Laupacis 2001, Blajchman 2001).
Conclusions 7.3.2.1
Primary cytomegalovirus (CMV) infection can be transmitted via blood
components and can result in severe complications in certain patient
Level 3
groups.
C
Level 3
Hamprecht 2001
Laupacis 2001
Other considerations
To date, leukocyte reduction has been maintained as the intervention of choice for the
preparation of CMV-safe cellular blood components.
In the case of intra-uterine transfusions, the treating experts wish to administer blood that is
leukocyte-reduced AND anti-CMV serology negative.
Recommendations 7.3.2.1
1. If a primary cytomegalovirus (CMV) infection in the recipient of a blood component is
likely, this should also be reported to Sanquin Blood Supply.
2. Leukocyte-reduced blood components are considered CMV-safe (see also Chapter 2),
but in order to avoid all risks during intra-uterine transfusions the donor should also
be anti-CMV seronegative.
Level 4
Zaaijer 2004,
Gezondheidsraad 2002
307
Recommendation 7.3.2.2
B19-safe components must be requested for patients with an increased risk of severe
detrimental consequences of a B19 infection from transfusion of standard short shelf-life
blood components (see Chapter 2, paragraph 2.6).
Level 2
308
For the Netherlands, the remaining chance of infection with HBV through
transfusion of a short shelf-life blood component can be calculated as 1 per
800,000 donor units and for HCV (after the implementation of the nucleic
acid amplification test (NAT)) as 1 per 3 million donor units.
A2
Level 4
SHOT 2007
Recommendations 7.3.2.3
1.
In the case of viral hepatitis, the (small) possibility of transmission by a blood
transfusion should also be considered.
2.
Each case of viral post-transfusion hepatitis (PTH) for example by HBV or HCV
with a positive blood transfusion history should also be reported to Sanquin Blood
Supply.
59 excl. NAT
1.27
309
HIV
11 incl. NAT
0.59
0.02
HCV
12 incl. NAT
0.71
0.02
Conclusions 7.3.2.4
The risk of HIV transmission by transfusion of blood cells is very low in the
Netherlands, partly due to thorough donor selection procedures and is
currently estimated at 1 in 5 million.
Level 3
C
Goodnough 1999; Glynn 2000,
D
Jaaroverzichten Sanquin Bloedvoorziening
Level 4
The risk of HIV transmission by transfusion of fresh frozen plasma secured according to the quarantine method or inactivated by SD treatment
is negligible in the Netherlands.
D
Recommendations 7.3.2.4
1.
2.
In the case of an HIV infection, the recipients transfusion history over the past 10
years should be checked.
Each case of HIV infection with a positive blood transfusion history should also be
reported to Sanquin Blood Supply.
Recommendation 7.3.3
In the case of malaria in a recipient of erythrocyte transfusions, the (extremely small)
possibility of post-transfusion malaria must be considered if other causes have been ruled
out.
7.3.4 Post-transfusion variant Creutzfeldt Jakob Disease (vCJD) infection
Scientific support
Creutzfeldt Jakob Disease (CJD) belongs to a group of conditions called Transmissible
Spongiform Encephalopathies (TSE), which are characterised by a long to very long
incubation period and severe, irreversible damage to the central nervous system, resulting
in, among other conditions, dementia (Collins 2004).CJD has an incidence of approximately
1 per million inhabitants and the disease starts at an average age of 65 years.
CJD has been shown in a number of case control, look back and surveillance studies not be
be transmitted by blood or plasma components (Dorsey 2009).
Since the early 1980s, bovine spongiform encephalopathy (BSE) has been increasingly
detected . in cattle in the United Kingdom (UK) and later also in various other countries.
Following measures in the cattle breeding and food industry, the incidence was strongly
reduced. Subsequently since 1996, a number of patients particularly in the United
Kingdom have been diagnosed with an abnormal (variant) form of CJD (vCJD). By the end
of 2008, a total of over 160 people in the United Kingdom had died of vCJD. Animal
experiments have shown that this variant form of CJD vCJD can be transmitted by blood
(Collins 2004).
In December 2003, the first possible case of transmission of vCJD by blood transfusion in
humans was reported in the United Kingdom. This transfusion of an erythrocyte concentrate
took place in 1996 when the donor was still healthy. After the donor died of vCJD in 2000,
the recipient of his blood was also diagnosed with vCJD in 2003. Since then, a further two
cases of vCJD have been diagnosed in the United Kingdom in recipients of (non-leukocyte
reduced) erythrocyte concentrates, obtained from donors who developed vCJD after their
donation (Hewitt 2006). Although it is theoretically plausible that the disease was caused in
all individuals by the consumption of contaminated beef components, the chance that
transmission occurred via blood is statistically much greater. In a fourth recipient of an
erythrocyte concentrate from a contaminated donor, prion proteins characteristic of vCJD
were found in the spleen after her death . (Hewitt 2006). To date, three cases of vCJD have
been diagnosed in the Netherlands; these people were neither blood donor, nor had they
ever received blood components (Health Care Inspectorate 2010).
Since there is no inactivation method yet and there is no reliable screening test or
confirmation test for tracing vCJD in blood, two precautionary measures have been taken in
the Netherlands to limit the risk of transmission of vCJD via blood and blood components
(van Aken 2001). These are:
- Donor exclusion, i.e. rejecting donors who resided in the United Kingdom for a period of
six months or more between 1980 and 1996 (since 2001) and donors who have
themselves received an allogeneic blood transfusion since 1980 (since 2005).
Blood Transfusion Guideline, 2011
311
Level 3
Foster 2000
Recommendation 7.3.4
If the diagnosis of Creutzfeldt Jakob Disease (CJD) or variant Creutzfeldt Jakob Disease
(vCJD) is made, one should verify whether the patient ever received a transfusion of blood
components and whether he/she ever donated blood. If yes, this should be reported to the
Health Care Inspectorate and in the case of blood donation also to Sanquin Blood Supply.
Literature 7.1.2
1.
Literature 7.2.1
1.
2.
3.
4.
312
5.
6.
Literature 7.2.2
1.
2.
Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th edition. 1998. Montgomery Scientific
Publications, Durham NC.
Redman M, Regan F, Contreras M. A prospective study of the incidence of red cell alloimmunisation following transfusion. Vox Sang 1996;71:216-20.
Literature 7.2.3
1.
2.
3.
4.
5.
6.
7.
Council of Europe Publishing. Guide to the preparation, use and quality assurance of blood
components. 13th Ed, 2007; ISBN 978-92-871-6137-6.
Gilstad CW. Anaphylactic transfusion reactions. Curr. Opin. Hematol 2003 10:419-423.
Sandler SG, Mallory D, Malamut D, Eckrich R. IgA anaphylactic transfusion reactions.
Transfus Med Rev 1995;9:1-8. Review.
Shimada E, Tadokoro K, Watanabe Y, Ikeda K, Niihara H, Maeda I et al. Anaphylactic
transfusion reactions in haptoglobin-deficient patients with IgE and IgG haptoglobin
antibodies. Transfusion 2002; 42:766-773.
TRIP Rapport 2007. ISBN 978-90-78631-04-0
Vamvakas EC. Allergic and anaphylactic reactions. In: Popovsky MA (ed). Transfusion
reactions, 3e ed. Bethesda, MD: AABB Press, 2007. ISBN 978-1-56395-244-9: 105-156.
Yuan S, Goldfinger D. A readily available assay for anti-immunoglobulin A: is this what we
have been waiting for? Transfusion 2008 Oct 48(10):2048-50.
Literature 7.2.4
1.
2.
3.
4.
5.
6.
7.
8.
Kerkhoffs JL, Eikenboom JC, Schipperus MS, van Wordragen-Vlaswinkel RJ, Harvey MS, de
Vries RR et al, A multicenter randomised study of the efficacy of transfusions with platelets
stored in platelet additive solution II versus plasma. Blood 2006; 108(9) 3210-5.
Kluter H, Bubel S, Kirchner H, Wilhelm D. Febrile and allergic transfusion reactions after the
transfusion of white cell-poor platelet preparations. Transfusion 1999;39:1179-84.
Patterson BJ, Freedman J, Blanchette V, Sher G, Pinkerton P, Hannach B, et al. Effect of
premedication guidelines and leukoreduction on the rate of febrile nonhaemolytic platelet
transfusion reactions. Transfus Med 2000;10:199-206.
Rebibo D, Simonet M, Hauser L. Introduction of platelet additive solution in platelet
concentrates: towards a decrease in blood transfusion reactions. Transfus Clin Biol 2008;
15(5): 285-93.
Sarkodee-Adoo CB, Kendall JM, Sridhara R, Lee EJ, Schiffer CA. The relationship between
the duration of platelet storage and the development of transfusion reactions. Transfusion
1998;38:229-35.
Transfusion-associated red eye syndrome. Centers for disease control and prevention.
Haematologica 1998;83:288.
Uhlmann EJ, Isgriggs E, Wallhermfechtel M, Goodnough LT. Prestorage universal WBC
reduction of RBC units does not affect the incidence of transfusion reactions. Transfusion
2001;41:997-1000.
Vamvakas EC. Allergic and anaphylactic reactions. in: Transfusion reactions. Popovsky MA
(ed). Bethesda, MD: 3rd edition 2007, AABB Press, ISBN 978-1-56395-244-9.
Literature 7.2.5
1.
2.
Heddle NM, Klama LN, Griffith L, Roberts R, Shukla G, Kelton JG. A prospective study to
identify the risk factors associated with acute reactions to platelet and red cell transfusions.
Transfusion 1993;33:794-7.
Heddle NM. Febrile nonhemolytic transfusion reactions. In: Popovsky MA (ed). Transfusion
reactions 3rd edition. Bethesda, MD: AABB Press 2007. p. 57-103. .
313
3.
4.
5.
6.
Heddle NM. Noninfectious adverse reactions to blood transfusion. In: Brain MC, Carbone PP
(eds). Current therapy in hemato-oncology. St. Louis: Mosby-Year book, 1995. p. 225-30.
Kennedy LD, Case LD, Hurd DD, Cruz JM, Pomper GJ, a prospective, randomized doubleblind controlled trial of acetaminopen and diphenhydramine pretransfusion medication for the
prevention of transfusion reactions. Transfusion 2008; 48:2285-2291.
Muylle L, Wouters E, Bock R de, Peetermans ME. Reactions to platelet transfusion: The
effect of the storage time of the concentrate Transfus Med 1992;2:289-93.
Williamson LM, Lowe S, Love EM, Cohen H, Soldan K, McClelland DBL, et al. Serious
Hazards of Transfusion (SHOT) initiative analyses of the first two annual reports. BMJ
1999;319:16-9.
Literature 7.2.6
1.
2.
3.
4.
5.
6.
7.
8.
Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood
transfusion. Vox Sanguinis 2005; 89:1-10.
Fatalities Reported to FDA Following Blood Collection and Transfusion, Annual Summary for
Fiscal Year 2008
Goldman M, Webert KE, Arnold DM, Freedman J, Hannan J, Blajchman MA, TRALI
consensus panel. Proceedings of a consensus conference: towards an understanding of
TRALI. Transfus Med Rev 2005; 19: 2-31.
Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S et al. Toward an
understanding of transfusion-related acute lung injury: statement of a consensus panel.
Transfusion 2004; 44: 1774-1789.
Kopko PM and Popovsky MA. Transfusion-Related Acute Lung Injury. In: Popovsky MW, ed.
Transfusion Reactions, 3rd Edition, AABB Press, 2007.
Palfi M, Berg S, Ernerudh J, Berlin G. A randomized controlled trial of transfusion-related
acute lung injury: is plasma from multiparous blood donors dangerous? Transfusion
2001;41:317-22.
SHOT Annual Report 2007, www.shotuk.org
TRIP Rapport 2007, ISBN 978-90-78631-04-0, www.tripnet.nl
Literature 7.2.7
1.
2.
3.
4.
5.
6.
7.
8.
9.
314
Affsaps,
Rapport
Hmovigilance
2007.
Gedownload
juni
2009
op
http://www.afssaps.fr/var/afssaps_site/storage/original/application/e92822f8ff7cb27d5f2009c9
ac27bf1c.pdf
Audet AM, Andrzejewski C, Popovsky MA. Red blood cell transfusion practices in patients
undergoing orthopaedic surgery: a multi-institutional analysis. Orthopedics 1998;21:851-64.
Center for Biologics Evaluation and Research. Fatalities reported to FDA. Following blood
collection & transfusion. Annual summary for fiscal years 2005 and 2006. Rockville: CBER;
2008. Available from http://www.fda.gov/Cber/ blood/fatal0506.htm
Gajic 0, Gropper MA, Hubmayr RD. Pulmonary edema after transfusion: How to differentiate
transfusion-associated circulatory overload from transfusion-related acute lung injury. Crit
Care Med 2006; 34, 5: 109-13
Li G, Daniels CE, Kojicic M, Krpata T, Wilson GA, Winters JL, Moore SB, Gajic O. The
accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal-ebpro-brain naturietic
peptide) in the differentiation between transfusion-related acute lung injury and
transfusionrelated circulatory overload in the critically ill. Transfusion 2009;49:13-20.
Popovsky MA, Taswell HF. Circulatory overload: an underdiagnosed consequence of
transfusion [Abstract]. Transfusion 1985;25:469.
Popovsky MA. Circulatory overload. In: Popovsky MA, editor. Transfusion reactions. 3rd ed.
Bethesda: American Association of Blood Banks; 2007. p. 331-40.
Rana R, Fernandez-Perez E, Khan SA. Transfusion-related acute lung injury and pulmonary
edema in critically ill patients: a retrospective study. Transfusion 2006;46:1478-83.
Robillard B, Itaj NK, Chapdelaine A. Increasing incidence of transfusion-associated circulatory
overload reported to the Quebec Hemovigilance System, 2000-2006. Transfusion 2008; 48
Suppl:204A.
Blood Transfusion Guideline, 2011
Literature 7.2.8
1.
2.
3.
4.
5.
6.
7.
8.
9,
Literature 7.2.9
1.
2.
3.
4.
5.
6.
American Association Blood Banks. Guidelines and Standards for Blood Banks and
Transfusion Services, 25th edn. AABB Press : Bethesda, 2006. (26e editie is in concept)
Dwyre DM, Holland PV. Transfusion-associated graft-versus-host disease. Vox Sang. 2008;
95(2): 85-93
Guide to the preparation, use and quality assurance of blood components, 14e editie, 2008,
Raad van Europa
Hayakawa S, Chishima F, Sakata H, Fujii K, Ohtani K, Kurashina K, et al. A rapid molecular
diagnosis of posttransfusion graft-versus-host disease by polymerase chain reaction.
Transfusion 1993;33:413-7.
Ohto H, Anderson KC. Survey of transfusion-associated graft-versus-host disease in
immunocompetent recipients [Review]. Transfus Med Rev 1996;10:31-43.
Williamson LM, Stainsby D, Jones H, Love E, Chapman CE, Navarrete C, Lucas G, Beatty C,
Casbard A, Cohen H. The impact of universal leukodepletion of the blood supply on
hemovigilance reports of posttransfusion purpura and transfusion-associated graft-versushost disease. Transfusion. 2007;47(8):1455-67.
Literature 7.2.10
1.
2.
3.
4.
Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron
overload-releated disease in HFE hereditary hemochromatosis. N Eng J Med 2008; 358: 22130
Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986 95
Borgna-Pignatti C, Cappelini MD, De Stefano P. Del Vecchio GC, Forni GL, Gamberrini MR,
et al. Survival and complications in thalassemia. Ann N Y Acad Sci 2005; 1054: 40 7.
Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. An J Med 1971; 51:
209-
315
5.
6.
7.
8.
9.
10.
Deugnier Y, Brissot P, Loreal O. Iron and the liver: update 2008. J Hepatol 2008; 48: S113
23
Malcovati L. Impact of transfusion dependency and secondary iron overload on the survival of
patients with myelodysplastic syndromes. Leuk Res 2007; 31: S 2 6
Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the
UK Thalassaemia Register. Lancet 2000, 355: 2051-2.
Piga A, Galanello R, Forni GL, Capellini MD, Origa R, Zappu A, et al. Randomized phase II
trial of deferasirox (Exjade, ICL670), a once-dialy, orally-administrated iron chelator, in
comparison to deferoxamine in thalassemia patients with transfusional iron overload.
Haematologica 2006; 91: 873 80.
Roberts DJ,Rees D,Howard J et al .Desferrioxamine mesylate for managing transfusional iron
overload in people with transfusion-dependent thalassaemia.Cohrane database of systematic
reviews 2005;CD004450.
Wood JC, Ghugre N. Magnetic resonance assessment of excess iron in thalassemia, sickle
cell disease and other iron overload diseases. Hemoglobin 2008; 32: 85 96.
Literature 7.2.11
1.
2.
3.
Marwijk Kooy M van, Prooijen HC van, Moes M, Bosma-Stants I, Akkerman JW. Use of
leukocyte-depleted platelet concentrates for the prevention of refractoriness and primary HLA
alloimmunization: a prospective, randomised trial. Blood 1991;77:201-5.
Schnaidt M, Northoff H, Wernet D. Frequency and specificity of platelet-specific alloantibodies
in HLA-immunized haematology-oncologic patients. Transfus Med 1996;2:111-4.
Sintnicolaas K, Marwijk Kooij M van, Prooijen HC van, Dijk BA van, Putten WLJ van, Claas
FHJ, et al. Leukocyte depletion of random single donor platelet transfusions does not prevent
secondary HLA-alloimmunization and refractoriness: a randomized prospective study. Blood
1995;85:824-8.
Literature 7.2.12
1.
2.
3.
4.
5.
6.
7.
8.
316
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Tartter PI, Mohandas K, Azar P, Endres J, Kaplan J, Spivack M. Randomized trial comparing
packed red cell blood transfusion with and without leukocyte depletion for gastrointestinal
surgery. Am.J.Surg. 1998;176(5):462-6.
Titlestad IL, Ebbesen LS, Ainsworth AP, Lillevang ST, Qvist N, Georgsen J. Leukocytedepletion of blood components does not significantly reduce the risk of infectious
complications. Results of a double- blinded, randomized study. Int.J.Colorectal.Dis.
2001;16(3):147-53.
van Hilten JA, van de Watering LM, van Bockel JH, van de Velde CJ, Kievit J, Brand R, van
den Hout WB, Geelkerken RH, Roumen RM, Wesselink RM, et al. Effects of transfusion with
red cells filtered to remove leucocytes: randomised controlled trial in patients undergoing
major surgery. BMJ 2004 May 29;328(7451):1281.
Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update.
Blood Rev. 2007 Nov;21(6):327-48.
van de Watering LM, Hermans J, Houbiers JG, van den Broek PJ, Bouter H, Boer F, Harvey
MS, Huysmans HA, Brand A. Beneficial effects of leukocyte depletion of transfused blood on
postoperative complications in patients undergoing cardiac surgery: a randomized clinical
trial. Circulation 1998 Feb 17;97(6):562-8.
Wallis JP, Chapman CE, Orr KE, Clark SC, Forty JR. Effect of WBC reduction of transfused
RBCs on postoperative infection rates in cardiac surgery. Transfusion 2002 Sep;42(9):112734.
Bracey AW, Radovancevic R, Nussmeier NA, Houston S, LaRocco M, Vaughn WK, Cooper
JR. Leukocyte-reduced blood in open-heart surgery patients: effects on outcome. Transfusion
2002;42 (Suppl):5S.
Boshkov LK, Furnary A, Morris C, Chien G, van Winkle D, Reik R. Prestorage leukoreduction
of red cells in elective cardiac surgery: results of a double-blind randomized controlled trial.
Blood 2004;104:112a.
Bilgin YM, van de Watering LM, Eijsman L, Versteegh MI, Brand R, van Oers MH, Brand A.
Double-blind, randomized controlled trial on the effect of leukocyte-depleted erythrocyte
transfusions in cardiac valve surgery. Circulation 2004 Jun 8;109(22):2755-60.
Blumberg N, Zhao H, Wang H, Messing S, Heal JM, Lyman GH. The intention-to-treat
principle in clinical trials and meta-analyses of leukoreduced blood transfusions in surgical
patients. Transfusion 2007 Apr;47(4):573-81.
Vamvakas EC. White-blood-cell-containing allogeneic blood transfusion and postoperative
infection or mortality: an updated meta-analysis. Vox Sang. 2007 Apr;92(3):224-32.
Gantt CL. Red blood cells for cancer patients. Lancet 1981;2(8242):363.
Blumberg N, Heal JM. Transfusion and host defenses against cancer recurrence and
infection. Transfusion 1989;29(3):236-45.
Amato A, Pescatori M. Perioperative blood transfusions for the recurrence of colorectal
cancer. Cochrane.Database.Syst.Rev. 2006 Jan 25;(1):CD005033.
Opelz G, Mickey MR, Terasaki PI. Identification of unresponsive kidney-transplant recipients.
Lancet 1972 Apr 22;1(7756):868-71.
Vincenti F, Duca RM, Amend W, Perkins HA, Cochrum KC, Feduska NJ, Salvatierra O, Jr.
Immunologic factors determining survival of cadaver-kidney transplants. The effect of HLA
serotyping, cytotoxic antibodies and blood transfusions on graft survival. N.Engl.J.Med. 1978
Oct 12;299(15):793-8.
Opelz G, Vanrenterghem Y, Kirst G, Gray DW, Horsburgh T, Lachance JG, Largiader F,
Lange H, Vujaklija-Stipanovic K, Alvarez-Grande J, Schott W, Hoyer J, Schnuelle P,
Descoeudres C, Ruder H, Wujciak T, Schwarz V. Prospective evaluation of pretransplant
blood transfusions in cadaver kidney recipients. Transplanatation 1997 april 63;(7):964-967
Alexander JW, Light JA, Donaldson LA, Delmonico FL, Diethelm AG, Wilkinson A, Rosenthal
JT, Thistlethwaite JR, Hunsicker LG, Matas AJ, First MR, Reinsmoen NL, Rose SM.
Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporin a in non-HLA
identical living kidney transplant recipients. Trasnplantation 1999;68(8):1117-1124
van der Mast BJ, Balk AH. Effect of HLA-DR-shared blood transfusion on the clinical outcome
of heart transplantation. Transplantation 1997 May 27;63(10):1514-9.
317
28.
29.
30.
31.
32.
33.
34.
Katz MR, Barnhart GR, Goldman MH, Rider S, Hastillo A, Szentpetery S, Wolfgang TC, Hess
ML, Mohanakumar T, Lower RR. Pretransplant transfusions in cardiac allograft recipients.
Transplantation 1987 Apr;43(4):499-501.
Koneru B, Harrison D, Rizwan M, Holland BK, Ippolito T, Holman MJ, Leevy CB. Blood
transfusions in liver recipients: a conundrum or a clear benefit in the cyclosporine/tacrolimus
era? Transplantation 1997 Jun 15;63(11):1587-90.
Waanders MM, Roelen DL, de Fijter JW, Mallat MJ, Ringers J, Doxiadis II, Brand A, Claas
FH. Protocolled blood transfusions in recipients of a simultaneous pancreas-kidney transplant
reduce
Hjalgrim H, Edgren G, Rostgaard K, Reilly M, Tran TN, Titlestad KE, Shanwell A, Jersild C,
Adami J, Wikman A, et al. Cancer incidence in blood transfusion recipients. J.Natl.Cancer
Inst. 2007 Dec 19;99(24):1864-74.
Cerhan JR, Engels EA, Cozen W, Davis S, Severson RK, Morton LM, Gridley G, Hartge P,
Linet M. Blood transfusion, anesthesia, surgery and risk of non-Hodgkin lymphoma in a
population-based case-control study. Int.J.Cancer 2008 Aug 15;123(4):888-94.
Erber E, Lim U, Maskarinec G, Kolonel LN. Common immune-related risk factors and incident
non-Hodgkin lymphoma: The multiethnic cohort. Int.J.Cancer 2009 Mar 25.
Houbiers 1991(?)..,Proefschrift Universiteit Leiden
Literature 7.3.1
1.
2.
3.
4.
5.
Blajchman MA. Bacterial contamination and proliferation during the storage of cellular blood
products. Vox Sang. 1998;74 Suppl 2:155-9.
de Korte D, Curvers J, de Kort WL, Hoekstra T, van der Poel CL, Beckers EA et al. Effects of
skin disinfection method, deviation bag and bacterial screening on the clinical safety of
platelet transfusions in the Netherlands. Transfusion 2006; 46:476-485.
Rapport bacterile contaminatie van bloedproducten. Amsterdam: Stichting Sanquin
Bloedvoorziening, 2001. P.4-6.
TRIP Rapport 2007, TRIP 2008, ISBN 978-90-78631-04-1.5.
Schrezenmeier, H., Walther-Wenke, G., Mller, T., Weinauer, F., Younis, A., Holland-Letz, T.,
Geis, G., Asmus, J., Bauerfeind, U., Burkhart, J., Deitenbeck, R., Frstemann, E., Gebauer,
W., Hchsmann, B., Karakassopoulos, A., Liebscher, U.-M., Snger, W., Schmidt, M.,
Schunter, F., Sireis, W. and Seifried, E. (2007), Bacterial contamination of platelet
concentrates: results of a prospective multicenter study comparing pooled whole blood
derived platelets and apheresis platelets. Transfusion, 47: 644652. doi: 10.1111/j.15372995.2007.01166.x
Literature 7.3.2
1.
2.
Literature 7.3.2.1
1.
2.
3.
4.
5.
318
Adler SP. Data that suggest that FFP does not transmit CMV. Transfusion 1988;28:604.
Blajchman MA, Goldman M, Freedman JJ, Sher GD. Proceedings of a consensus
conference: prevention of posttransfusion CMV in the era of universal leukoreduction.
Transfus Med Rev 2001;15:1-20.
Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M, Schnoch G, et al. A comparison of
filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the
prevention of transfusion-associated CMV infection after marrow transplant. Blood
1995;86:3598-603.
Hamprecht K, Maschmann J, Vochem M, Dietz K, Speer CP, Jahn G. Epidemiology of
transmission of cytomegalovirus from mother to preterm infant by breastfeeding. Lancet
2001;357:513-8.
Ho M. Cytomegalovirus. In: Mandell GL, Bennet JE, Dolin R. Principles and practice of
Infectious Diseases. New York: Livingstone, 1995.
6.
7.
8.
9.
10.
11.
James DJ, Sikotra S, Sivakumaran M, Wood JK, Revill JA, Bullen V, et al. The presence of
free infectious cytomegalovirus (CMV) in the plasma of donated CMV-seropositive blood and
platelets. Transfus Med 1997;7:123-6.
Kuhn JE. Transfusion-associated infections with cytomegalovirus and other human
herpesviruses. Infus Ther Transfus Med 2000;27:138-43.
Laupacis A, Brown J, Costello B, Delage G, Freedman J, Hume H, et al. Prevention of posttransfusion CMV in the era of universal WBC reduction: a consensus statement [Review].
Transfusion 2001;41:560-9.
Preiksaitis JK. The cytomegalovirus-safe blood product: is leukoreduction equivalent to
antibody screening? Transfus Med Rev 2000;14:112-36.
Smith KL, Cobain T, Dunstan RA. Removal of cytomegalovirus DNA from donor blood by
filtration. Br J Haematol 1993:83:640-2. 7. Roback JD, Bray RA, Hilyer CD. Longitudinal
montoring of WBC subsets in packed RBC units after filtration: implications for transfusion
transmission of infections. Transfusion 2000;40:500-6.
Ho M. The history of cytomegalovirus and its diseases. Med Microbiol Immunol. 2008
Jun;197(2):65-73
Literature 7.3.2.2
1.
2.
3.
4.
5.
6.
7.
de Haan TR, de Jong EP, Oepkes D, Vandenbussche FP, Kroes AC, Walther FJ, Infectie met
het humaan parvovirus B19 (vijfde ziekte) in de zwangerschap: voor de foetus soms
levensbedreigend. Ned. Tijdschr. Geneeskd 2008; 152 (21): 1185-90.
Gezondheidsraad. Bloedproducten en Parvovirus B19. Den Haag: Gezondheidsraad 2002;
publicatie nr 2002/07. ISBN: 90-5549-432-1.
Kleinman SH, Glynn SA, Lee TH, Tobler L, Montalvo L, Todd D et al, Prevalence and
quantitation of parvovirus B19 DNA Levels in blood donors with a sensitive polymerase chain
reaction screening assay. Transfusion 2007; 47(10): 1745-50.
Plentz A, Hahn J, Knll A, Holler D, Jilg W en Modrow S, Exposure of hematolgoic patients to
parvovirus B19 as a contaminant of blood cell preparations and blood products. Transfusion
2005; 45 (11) 1811-5.
Schmidt M, Themann A, Drexler C, Bayer M, Lanzer G, Menichetti E, et al, Blood donor
screening for parvovirus B19 in Germany and Austria. Transfusion 2007; 47(10):1775-82.
van Dam IE, Kater AP, Hart W en van den Born BJ, Ernstige anemie door infectie met het
humaan Parvovirus B19 bij een patint met een auto-autoimmuun hemolytische anemie en
een B-cel non-Hodgkin lymfoom. Ned. Tijdschr. Geneeskd 2008; 152(3): 153-7.
Zaaijer HL, Koppelman MH en Farrington CP. Parvovirus B19 viraemia in Dutch blood
donors. Epidemiol Infect 2004; 132:1161-6.
Literature 7.3.2.3
1. Bij van der AK, Coutinho RA, van der Poel CL. Surveillance of risk profiles among new and
repeat blood donors with transfusion-transmissible infections from 1995 through 2003 in the
Netherlands. Transfusion 2006; 46(10):1729-1736.
2. Glynn SA, Kleinman SH, Schreiber GB, Busch MP, Wright DJ, Smith JW, et al. Trends in
incidence and prevalence of major transfusion-transmissible viral infections in US blood
donors, 1991 to 1996. JAMA 2000;284:229-35.
3. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two
parts-blood transfusion. N Engl J Med 1999;340:438-47.
4. Poel CL van der, Ebeling F. Hepatitis C virus: epidemiology, transmission and prevention. In:
Reesink HW (ed). Hepatitis C virus. Current Studies in Hematology and Blood Transfusion.
Basel: Karger, 1998.no 62, p. 208-36.
5. Richtlijn Laboratorium Onderzoek op Infecties, Stichting Sanquin Bloedvoorziening. 2009
6. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral
infections. N Engl J Med 1996;334:1685-90.
7. Serious Hazards of Transfusion (SHOT) Report 2007, www.shotuk.org.
319
Literature 7.3.2.4
1.
2.
3.
4.
Glynn SA, Kleinman SH, Schreiber GB, Busch MP, Wright DJ, Smith JW, et al. Trends in
incidence and prevalence of major transfusion-transmissible viral infections in US blood
donors, 1991 to 1996. JAMA 2000;284:229-35.
Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two
parts-blood transfusion. N Engl J Med 1999;340:438-47.
Jaaroverzichten Stichting Sanquin Bloedvoorziening 2000-2009
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral
infections. N Engl J Med 1996;334:1685-90.
Literature 7.3.3
1.
2.
3.
4.
Drukker W, de Vries SI. Entmalaria door bloedtransfusie, 1950. NTVG 94: 3310-3313.
Eliades MJ, Shah S, Nquyen-Dinh P, Newman RD, Barber AM, et al. Malaria surveillance-United States, 2003. : Jun 3;54(2):25-40
Kitchen AD, Barbara JA, Hewitt PE. Documented cases of post-transfusion malaria occurring
in England: a review in relation to current and proposed donor-selection guidelines.Vox
Sanquinis 2005 Aug;89(2):77-80.
Nahlen BL, Lobel HO, Cannon SE, Campbell CC. Reassessment of blood donor selection
criteria for United States travellers to malarious areas. Transfusion 1991;31:798-804.
Literature
1.
2.
3.
4.
5.
6.
7.
320
Aken WG van. Variant van de Ziekte van Creutzfeldt-Jakob en bloedtransfusie; rapport van
de Gezondheidsraad [review]. Ned Tijdschr Geneeskd 2001;145:1444-7.
Collins SJ, Lawson VA, Masters CL. Transmissible spongiform encephalopathies. Lancet
2004;363:51-61.
Dorsey K, Zou S, Schonberger LB, Sullivan M, Kessler D, Notari E 4th et al. Lack of evidence
of transfusion transmission of Creutzfeldt-Jakob disease in a US surveillance study.
Transfusion 2009 Jan 5 (epub).
Foster PR. Studies on the removal of abnormal prion protein by processes used in the
manufacture of human plasma products. Vox Sang 2000;78:86-95
Health
Protection
Agency.
2009,
informatie
juni
2009
gedownload
op
http://www.hpa.org.uk/webw/HPAweb&HPAwebPrinterFriendly/HPAweb_C/1195733818681?
p=1225960597236
Hewitt PE, Llewellyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood
transfusion: results of the UK Transfusion Medicine Epidemiological Review Study. Vox Sang.
2006; 91:221-30.
www.igz.nl
Pre-operative treatment of any existing anaemia (see Chapter 4 and for a recent
review: Goodnough 2010)
321
Laser surgery
A laser burner works according to the same principles as an electrocautery, but it uses laser
energy instead of electrical current to separate tissues and simultaneously coagulate
(Wyman 1993, Cornford 1997).
Water jet dissector
The water jet dissector is an instrument that uses water at high pressure to separate tissues
and causes relatively little tissue damage (Rau 1995, Baer 1993, Wu 1992).
Ultrasonic dissector
An ultrasonic dissector is an instrument that uses the mechanical energy created by
ultrasonic vibrations to perform precise surgical incisions, which in combination with
controlled haemostasis limits the damage to surrounding tissues to a minimum (Hoenig
1996, Epstein 1998).
Local haemostatics
The local application of haemostatic pharmacological agents such as fibrin glue (see
8.1.3.4.) can limit blood loss during surgical procedures. Another option to halt localised
bleeding is infiltration with epinephrine (Kuster 1993, Sheridan 1999), phenylephrine or the
local application of cocaine (Berde 2000, Riegle 1992). The (capillary) bleeding can be
halted by the vaso-constrictive effect of these agents.
8.1.1.2 Minimally invasive surgical techniques
Minimally invasive surgical techniques can limit blood loss. These include surgical
techniques that limit the size of the procedure such as laparoscopy and thoracoscopy
and techniques that replace conventional surgery or limit the extent of the surgery, such as
endoluminal techniques and interventional radiology. Laparoscopy and thoracoscopy make
large incisions and extensive surgical dissection largely redundant, thereby reducing blood
loss and tissue damage (OReilly 1996, Caprotti 1998, Kerbl 1994). The last few years have
seen increasing use of radiological intervention to simplify, limit or even replace surgical
procedures. Examples are arterial embolisation, trans-jugular intrahepatic porto-systemic
shunts (TIPS) and stents.
For example, arterial embolisation of the iliac vessels can halt bleeding in a poly-trauma
patient with massive exsanguination shock. In the case of blunt injury to the spleen and liver,
the bleeding vessel can be traced and embolised with the aid of selective angiography
(Holting 1992, Ben-Menachem 1991, Agolini 1997, Willmann 2002, Spahn 2007). The
concept of damage control surgery combined with radiological intervention means that
severe trauma patients can be stabilised much faster and at an earlier stage. Definitive
(surgical) treatment can take place semi-electively at a later stage, once the patient is
haemodynamically and pulmonologically stable and any acidosis, electrolyte and clotting
abnormalities and hypothermia have been corrected (Beekley 2008, Spahn 2007). See also
Chapter 5.
Arterial embolisation can also be used for non-traumatic bleeding. During elective surgery,
pre-operative embolisation of a richly vascularised tumour can often limit the final resection
and minimise blood loss.
322
A trans-jugular intra-hepatic porto-systemic shunt (TIPS) can be used for bleeding from
oesophageal varices. The success rate is around 90% and this is a method where the blood
loss is controlled relatively quickly, which limits the number of blood transfusions and means
that surgical intervention can usually be avoided (McCormick 1994, Orloff 1994).
Radiological intervention is increasingly being used for both atherosclerotic stenosing
vascular disease and aneurysmatic vascular disease for the insertion of stents (also in
patients with increased cardio-pulmonary risk) and coils (also in patients with aneurysms of
cerebral vessels).
Cryo-surgery
This uses instruments that allow malignant tumours to be frozen to low temperatures (down
to minus 100 C) and then be removed. Cryo-therapy is much less invasive than
conventional surgery and is used primarily for liver and prostate surgery.
Radio-surgery
Developments both in the field of radiology and radiotherapy means that in some cases
malignancies can be treated using localised radiotherapy. An example of this is
brachytherapy as adjuvant treatment for breast cancer and . prevention of local tumour
recurrence in rectal and prostate cancer (Ragde 1998).
Conclusion 8.1.1
There are no studies available that demonstrate the efficacy of surgical
techniques to limit peri-operative blood loss.
Level 4
D
Recommendation 8.1.1
For each operation, one should consider defining a surgical strategy including the
accompanying surgical techniques to be used to limit the peri-operative blood loss.
8.1.2 Anaesthesiological measures to reduce peri-operative blood loss
Positioning of the patient/use of tourniquet
Careful positioning of the patient in order to prevent venous stagnation is a simple measure
that can be taken to reduce blood loss. (Simpson 1992). The use of a tourniquet to remove
blood from extremities is an efficient method of limiting blood loss in the surgical area
(Snyder 1997, Mathru 1996).
Normothermia
Maintaining a normal body temperature (normothermia) contributes to reducing blood loss.
Hypothermia reduces the function of both clotting factors and platelets (Drummond 2001).
This increases the tendency to bleed (Corazza 2000, Fries 2002, Spahn 2007, Eastridge
2006).
323
324
Conclusions 8.1.2
Careful positioning of the patient, aimed at preventing venous stagnation,
can limit peri-operative blood loss.
Level 4
D
Level 4
Level 1
Kleinschmidt 2001
Suttner 2001, Hersy 1997, Shapira 1997, Boldt 1999
Level 4
Level 4
Simpson 1992
Snyder 1997
Recommendations 8.1.2
The following anaesthesiology technique(s) should be applied or at least considered in
order to reduce peri-operative blood loss:
1.
Position the patient in such a way to prevent venous stagnation in the surgical area.
2.
Cooling of the patient should be avoided as much as possible.
3.
Consider controlled hypotension, preferably in combination with acute normovolemic
haemodilution (ANH) (see also 8.1.4).
4.
Where relevant: use blood removal techniques (tourniquet) and neuro-axial
techniques such as sympathetic nerve block.
8.1.3 Medicines
8.1.3.1 Aprotinin
During the BART study a randomised study of cardiac surgery patients with a high surgical
risk the interim analysis showed an increase in mortality (1.5x higher) and complications in
the group treated with aprotinin (Fergusson 2008). Therefore, the study was stopped. Partly
due to an analysis by the FDA of 67,000 files, it was then decided to remove aprotinin from
the market (Hiatt 2006, Fergusson 2008). As a result of this, the Medicines Evaluation Board
(MEB) consulted with the company Bayer and the Health Care Inspectorate in 2007 and
Blood Transfusion Guideline, 2011
325
decided that Trasylol (aprotinin) may no longer be used until the definitive analysis results
are known.
8.1.3.2 Tranexamic acid (Cyclokapron)
Properties and adverse effects
Tranexamic acid is a synthetic lysine analogue that exerts an anti-fibrinolytic effect by
reversibly blocking lysine binding sites on plasminogen (Dunn 1999, Fraser 2008). The
binding of both plasminogen and plasmin (which can still be formed) to fibrin are inhibited by
this. Tranexamic acid may also have an anti-inflammatory effect (Jimenez 2007).
Tranexamic acid is effective after both oral and intravenous administration. Tranexamic acid
is excreted by the kidneys.
Applications
Peri-operative
The use of tranexamic acid during cardiac surgery, orthopaedic procedures, during liver
transplants and prostate surgery significantly reduces blood loss, the number of blood
transfusions and the number of transfused patients (see table 8.1.3.2). The Cochrane
database in which 46 of the 53 studies used a transfusion protocol calculated that 1.12
fewer units of erythrocyte concentrate were transfused in the intervention arm of all included
studies. In the intervention arms of studies that did not use a transfusion protocol, the
number of allogeneic transfusions was higher than in the trials that determined the
transfusion indication based on a protocol (37 versus 25%) (Henry 2007).
The use of tranexamic acid during orthopaedic procedures is based on the fact that the use
of a tourniquet provides a bloodless peri-operative surgical field during knee surgery, but that
post-operative blood loss is amplified by local fibrinolysis activation (Engel 2001).
The use of tranexamic acid during prostate surgery is based on the fact that primary
fibrinolysis due to the release of plasminogen is one of the causes of peri-operative blood
loss.
Not much is known about the use of anti-fibrinolytics during liver resections. Elevated or
amplified fibrinolysis may occur during liver resections. During liver transplants, tranexamic
acid at a low dose suppresses fibrinolysis without reducing the number of blood transfusions,
in contrast to a high dose regime where the number of transfusions is thought to increase
(Groenland 2006, Molenaar 2007). See also table 8.1.3.2.
Gynaecology
Tranexamic acid is effective in women with menorrhagia caused by coagulopathies such as
von
Willebrand
Disease,
being
a
carrier
of
haemophilia
and
thrombocytopenia/thrombocytopathy due to menorrhagia caused by hormonal therapy or
peri-menopausal and other types of dysfunctional menorrhagias (Fraser 2008, Kadir 2006,
Bongers 2004, Duckitt 2007, Phupong 2006, Kriplani 2006). Tranexamic acid should not be
administered in the case of nephrogenic haematuria, because of possible urethral
thrombosis . The medication is also effective at inhibiting placental bleeding and post-partum
326
bleeding, as well as reducing blood loss during Caesarian sections and cervix surgery (Gai
2004, Martin-Hirsch 1999, Caglar 2008). See also table 8.1.3.2.
Neurosurgery/neurology
Reduction of recurrent bleeding (45%) following administration of tranexamic acid for subarachnoid haemorrhages has been described (Roos 2008, Liu-DeRyke 2008). See also
table 8.1.3.2.
However, the risk of cerebral ischaemia was elevated in five studies in the group treated with
anti-fibrinolytics, with considerable heterogeneity between the studies in which measures to
prevent ischaemia were taken (Roos 2008, Carley 2005).
As a result, tranexamic acid therapy does not improve the clinical result, because the benefit
of preventing recurrent bleeding does not outweigh the increase in consequences of cerebral
ischaemia. There are no data that support the routine use of tranexamic acid for this
indication.
Digestive tract bleeding
Older studies suggest that tranexamic acid reduces mortality with digestive tract bleeding. A
meta-analysis from 1989 of six studies showed a reduction in the number of operations by
40%, a reduction in mortality of 40% and a decrease in recurrent bleeding by 20 30%
(Henry 1989). Inclusion of a study with high mortality due to cimetidine use may have
distorted results (Gluud 2007). A recent meta-analysis revealed that tranexamic acid
reduces overall mortality (RR 0.61), but not blood loss, the bleeding-related mortality, the
number of transfusions or the number of operations (Gluud 2008).
Two case reports of two patients with GAVE (Gastric Antral Vascular Ectasia) describe that
the number of bleeding episodes and the number of blood transfusions decreased after
administration of tranexamic acid (Selinger 2008).
Side effects
Reported side effects of tranexamic acid use are vasospasm, gastro-intestinal symptoms,
orthostatic hypotension and thrombosis.
Gastro-intestinal symptoms (nausea, diarrhoea, stomach cramps) have only been described
with oral therapy (Faught 1998).
A change in skin colouration is occasionally reported. If this happens, treatment with the
medication should be stopped.
In the randomised studies performed to date in cardiac surgery, orthopaedics and liver
transplants, no significant difference was seen in the incidence of myocardial infarction,
thrombosis or cerebrovascular accidents (see table 8.1.3.2). This was confirmed by the large
retrospective studies by Mangano and Karkoutie and in the BART study. The use of
tranexamic acid therapy is also not associated with an increased short or long term mortality
(Mangano 2006 en 2007, Karkouti 2006, Fergusson 2008).
The administration of tranexamic acid with liver transplantation appears to be safe, without
elevated risk of thrombo-embolic complications (Molenaar 2007).
Clot formation in the bladder during trans-urethral prostatectomies (TURP) has been
described, as have fatal pulmonary emboli during retropubic prostatectomies. It is not clear
327
whether adequate thrombosis prophylaxis was given in these cases. The same applies to
patients with macroscopic haematuria.
Table 8.1.3.2: Reduction in the number of blood transfusions and side effects due to
tranexamic acid in meta-analyses and RCTs
Author (year)
Level
Study set-up
Reduction in
number of blood
transfusions3
Side effects
Brown (2007)
A1
RR 0.75
n.s.
Umscheid (2007)
A1
RR 0.65
vs AT RR 0.98
n.s.
Henry; (Cochrane
2007)
Jimenez (2007)
A1
RR 0.69 (EC)
n.s.
Non-cardiac; 21 RCT
orthopaedics; n = 993;
2 RCTLT n = 296
Ortho: RR 0.44
Menorrhagias; 7 RCT
1966 2004. n = 193
Surgery for cervical
intra-epithelial
neoplasia; 4 RCT 1966
1999. Prophylactic
TXA. (i.v. and/or oral);
n = 910
Reduction
BL: WMD 94%.
Reduction
secondary bleeding
OR 0.23
Reduction volume
BL 1 week:
55.66%
n.s.
BL up to 2 hours
post-partum 88 ml
less (p = 0.002)
Irregular
bleeding
stopped in week 1:
64.7 vs 35.3%
Only effect during
n.s.
Cardiac
surgery
B / A2
Inflammatory
response ; 17 vs
42% (p = 0.047)
Significant reduction
shock,
vasopressors,
artificial ventilation,
RD, D-dimer.
Orthopaedics
Henry; (Cochrane
2007)
A1
n.s.
LT: n.s.
Gynaecology
Lethaby;
(Cochrane 2000)
Martin-Hirsch;
(Cochrane 1999)
A1
A1
n.s.
A2
Phupong (2006)
A2
328
Caesarian
RCT TXA oral
n = 180
Bleeding in
implantations;
TXA oral vs
double blind;
section;
vs none;
Norplant
RCT
placebo;
1 week
n.s.
Kriplani (2006)
A2
Caglar GS (2008)
A2
use of TXA
BL reduction: 60.3
vs 57.7%
hysterectomy
17.8%
vs
n.s.
n.s.
outcome: no benefit
OR 1.12
Other
Roos (Cochrane
2008)
A1
Gluud (2008)
A1
Molenaar (2007)
A1
Sub-arachnoid
bleeding.
8
RCT
TXA
1966 2002;
n = 1360
Upper digestive
tract bleed. 7
RCT TXA vs
placebo; n =
1754.
LT: 1966 2005; 23
RCT;
n = 306
mortality: OR
0.99
n.s.
risk of ischaemia
increased in 5 trials:
OR
1.39,
with
heterogeneity in 1
study with ischaemia
prevention
(Roos
2000)
Hydrocephalus: n.s.
Mortality 5 vs 8%
Thrombo-emboli: n.s.
n.s.
1.
AT= Aprotinin Therapy; BL = Blood Loss; CABG = Coronary Artery Bypass Graft; EC =
Erythrocyte Concentrate; FFP = Fresh Frozen Plasma; i.v. = intravenous; LT = Liver Transplant;
n.s. = not significant; MPA = MedroxyProgesterone Acetate; OR = Odds Ratio; RCT =
Randomised Controlled Trial; RD = Renal Dysfunction; RR = Relative Risk; SMD =
Standardised Mean Difference; WMD = Weighted Mean Difference; U = Unit.
2.
All results are significant, unless specifically mentioned.
TXA versus control/placebo. Only the significant data were presented.
Conclusions 8.1.3.2
Tranexamic acid is a safe and effective agent to reduce blood loss and the
resulting number of allogeneic blood transfusions in cardiac surgery and
orthopaedic surgery and during liver transplants (with the exception of the
Level 1
hypo-fibrinolytic phase).
A1
329
Level 1
Roos 2008
Recommendations 8.1.3.2
1.
2.
3.
4.
5.
Peri-operative and post-operative use of tranexamic acid to reduce blood loss during
cardiac surgery and during knee and hip surgery is recommended.
Peri-operative use of tranexamic acid to reduce blood loss during liver transplants
should be considered except in the case of hyper-coagulability.
The administration of tranexamic acid to reduce blood loss should be considered in
the case of digestive tract bleeds, menorrhagia and post-partum bleeding.
Macroscopic haematuria is a contra-indication for tranexamic acid therapy with all the
above-mentioned indications.
Tranexamic acid administration is not recommended for trans-urethral prostatectomy
(TURP) and in the case of sub-arachnoid bleeding.
8.1.3.3 Desmopressin
Desmopressin is the synthetic analogue 1-deamino-8-D-arginine vasopressin (DDAVP) of
the hormone vasopressin. Following intravenous administration, desmopressin increased the
plasma concentration of von Willebrand Factor, factor VII and tissue plasminogen activator
by mobilisation from the storage sites. Depletion of the depots then takes place and the
clotting factors need to be produced once more. In addition, desmopressin has an antidiuretic effect without vaso-active side effects (Hashemi 1990).
Efficacy as blood saving method
Two meta-analyses (Laupacis 1997, Levi 1999), a Cochrane study (Henry 2001) and two
RCTs (Oliver 2000, Ozkizacik 2001) show that desmopressin administered peri-operatively
in cardiac surgery does not result in a decrease in the number of allogeneic blood
transfusions.
Conclusions 8.1.3.3
Following intravenous administration, desmopressin increases the plasma
concentration of von Willebrand factor, factor VIII and . tissue plasminogen
activator. In addition, desmopressin has an anti-diuretic effect without
Level 1
vaso-active side effects.
330
A1
Hashemi 1990
It has been shown that desmopressin does not reduce the number of
allogeneic blood transfusions in cardiac surgery.
Level 1
A1
A2
Other considerations
International guidelines recommend the use of desmopressin to improve platelet function in
patients using medication that inhibits platelet function (for example, Clopidogrel and
acetylsalicylic acid), in patients with uraemia, kidney or liver function abnormalities and in
patients with von Willebrand Disease types 1 and 2A (Ferrari 2007, Anonymous 2006; see
also Chapter 6.4.1).
331
A1
Carless 2009
Recommendation 8.1.3.4
The local application of fibrin glue is an option to reduce peri-operative blood loss.
Platelet-leukocyte enriched gel (PLG)
Definition
Platelet-leukocyte enriched gel (PLG) is a gelatinous mass that is formed within 10 seconds
when autologous platelet rich plasma (PRP) and thrombin are mixed. PRP is prepared
from the buffy coat, which in addition to platelets also contains a more than three-fold
higher concentration of leukocytes. The addition of thrombin activates the platelets in the
PRP and causes the release of various platelet growth factors (PDGF-ab, VEGF, EGF, TGFbeta) (Marx 2001).
Efficacy and use
In addition to use in wound healing, PLG also appears to be effective as a haemostatic and
could therefore result in fewer allogeneic blood transfusions (Everts Devilee 2006).
Area of application
In the early 1990s, PLG was positioned as an alternative to fibrin glue to improve
haemostasis in cardiac surgery patients (Ferrari 1987, Rubens 1998). However, the efficacy
of PLG as a haemostatic agent in cardiac surgery has not been examined in RCTs.
Incidental studies report that PLG reduced the use of allogeneic blood transfusions in
orthopaedic surgery (Everts Devilee 2006).
Conclusion 8.1.3.4
There are indications that in addition to a favourable effect on wound
healing platelet-leukocyte enriched gel (PLG) may also have a
haemostatic effect and might therefore result in fewer allogeneic blood
Level 3
transfusions.
C
Other considerations
There are no comparative studies on the efficacy and side effects of PLG and other local
haemostatics, . such as fibrin glue.
The use of bovine thrombin to activate PLG is not recommended, partly due to the
development of . antibodies (Chouhan 1997).
Recommendation 8.1.3.4
There is not enough data available to be able to make a recommendation concerning the
use of platelet-leukocyte enriched gel (PLG) as a local haemostatic.
332
333
Side effects
Hypertension
EPO can cause hypertension. The underlying mechanism is not well known, but an increase
in viscosity of the blood, the neutralisation of reflex hypoxic vasodilation or direct
vasoconstriction could be an explanation (Esbach 1991, Faught 1998).
Deterioration of pre-existing hypertension has been described during peri-operative use of .
high dose . EPO (3 of the 200 patients) (Laupacis 1998, Faught 1998). In all other studies,
no differences in complications were described for this indication between the study group
and the placebo group (Faught 1998). (see also table 8.1.3.5.)
Thrombo-embolic complications
EPO can cause thrombo-embolic complications (myocardial infarction, CVA, TIA) in patients
with renal failure. (Weiss 2005). The occurrence of these complications is described
separately for the various applications (see also table 8.1.3.5).
Contra-indications
Allergy to EPO or one of its ingredients, severe atherosclerosis of the coronary arteries or
peripheral vessels, uncontrolled hypertension, recent myocardial infarction, CVA or
cardiovascular conditions and situations in which a contra-indication for adequate antithrombotic prophylaxis exist are absolute contra-indications for pre-operative use of EPO
(Weiss 2005). Relative contra-indications are: epilepsy, chronic liver insufficiency and a
predisposition to deep vein thrombosis.
Applications
Cardiac surgery
A systematic review of nine randomised studies about the use of EPO in cardiac surgery
procedures alone or in combination with peri-operative autologous donation showed that
the use of EPO increases the number of autologous units of blood collected and significantly
reduces the number of allogeneic blood transfusions (Alghmadi 2006, Laupacis 1998).
There is not enough scientific data available to draw definitive conclusions about the risk of
thrombotic or vascular complications in this group of patients. Therefore, use in cardiac
surgery patients is often only advised in combination with pre-operative autologous donation
(PAD).
Orthopaedic surgery
An older systematic review of 21 randomised double blind studies shows that in orthopaedic
surgery, the pre-operative administration of EPO (sometimes in combination with PAD) also
caused a significant increase in the number of autologous units of blood collected and a
decrease in the use of allogeneic blood transfusions (Laupacis 1998). See also table 8.1.3.4.
No new meta-analysis has appeared since ., but several RCTs and one large observational
study do confirm the above-mentioned data (Moonen 2008, Rosencher 2005, Weber 2005,
Karkouti 2005).
Intravenous administration of EPO was not significantly more effective than subcutaneous
administration (odds ratio 0.52 and 0.32 respectively). The studies do not provide a clear
advice on the dosage (the most commonly used dosage was 600 IU/kg once a week).
334
There are indications that fewer injections are also effective (Rosencher 2005, Karkouti
2005), which could save on costs.
In the studies described above, no significantly increased risk of thrombo-embolic
complications was found.
Oncological surgery
EPO has been examined for various types of surgery, . with the aim of increasing the
preoperative Hb and reducing the number of peri-operative blood transfusions. A recent
meta-analysis demonstrated that for colorectal surgery EPO did not significantly reduce
the number of blood transfusions. There were no differences in mortality or morbidity
between the two groups (Devon 2009). This may be different for patients undergoing a
radical prostatectomy or a gynaecological radical surgery (Dousias 2005, Gaston 2006).
However, these studies were too small to be able to draw definitive conclusions.
People who reject transfusions for religious reasons
EPO (provided it is not dissolved in human albumin) is accepted by people who reject
transfusions on religious grounds (Ball 2008). See further 8.4 Jehovahs Witnesses.
Post-operative anaemia
For the treatment of post-operative anaemia, EPO combined with intravenous (i.v.) iron did
not appear to be more effective than i.v. iron or placebo therapy (Karkouti 2006).
Post kidney transplant
Following kidney transplantation, EPO resulted in a faster increase in Hb, after 4 months,
however . there were no differences compared to a placebo group. (Van Biesen 2005).
Another smaller study showed that . low dose EPO is sufficient in these patients (Baltar
2007). Erythropoietin did not affect the kidney function .
Pre-operative Autologous Donation (PAD)
Various studies have shown that EPO during PAD increases the number of units for
collection and results in a higher initial Hb immediately before and after surgery (see PAD
and extensive table 8.1.3.5 below) (Bovy 2006, Hyllner 2005, Hardwick 2004, Deutsch 2006,
Keating 2007).
Table 8.1.3.5: Data from clinical trials concerning the use of erythropoietin therapy aimed at
saving on peri-operative allogeneic blood transfusions
Author
(year)
Level
Study set-up1
Result2
Side effects2
A1
Meta-analysis 1966
1997.
Epo + PAD: 16 studies; 5
x cardio; 9 x ortho.
Epo + Ortho: 3 studies
Epo + cardio: 2 studies
Possibly more
thromboembolic
complications
in
several
small studies.
Not significant
Orthopaedics
Laupacis 1998
335
Moonen 2008
A2
Weber 2005
A2
RCT
Epo (4; n = 460) vs
control (n=235)
Karkouti 2005
Cardiac surgery
THP
- BT 7 vs 30%
TKP
- BT 0 vs 25%
At least 1 EC less
- BT 12 vs 46%
- Hb
- No effect: duration of
admission,
infections,
walking
BT + vs BT -:
- Walking: 3.8 vs 3.1 days
- Duration of admission:
12.9 vs 10.2 days
- BT 16.4 vs 56.1%
none
none
Alghamdi 2006
A1
Meta-analysis 11 RCTs
n=708
- Epo + PAD BT RR =
0.28
- Epo only: BT = 0.58
- Epo + PAD: OR chance
of 1 BT: 0.25
- Epo only: OR 0.25
Not significant
Laupacis 1998
A1
Meta-analysis 7 RCTs
A1
Meta-analysis colorectal
surgery 1966 2008. 4
RCTs
- No differences BT
A2
RCT.
Gyn.
radical
extripation. Epo n= 20,
control n=18
No difference
in
mortality,
thrombotic
complications.
None
Dousias 2005
Gaston 2006
A2
- Ht 4% higher
- BT = 4 vs 4%.
- QoL: n.s.
Oncological
surgery
Devon
2009
Cochrane
None
Pre-operative
Autologous
Donation
epo vs PAD
336
Hardwick 2004
A2
RCT ortho
Epo (2 x) n = 19 vs PAD n
= 21
+
cell
saver
intraoperative
Deutsch 2006
A2
Keating 2007
A2
RCT ortho
Epo (2 x) (n=25) vs PAD
(n = 25)
RCT ortho
Epo (4 x 600 U/kg)
(n=130) vs PAD (n=121)
BT trigger 8 g/dL also for
autologous
Rosencher 2005
None
None
None
A2
RCT
Epo (to Ht = 40%) vs PAD
(to Ht < 33%)
N = 93
Bovy 2006
A2
Hyllner 2005
A2
RCT orthopaedic
Epo (3 x 600 U/kg) + PAD
n=11 vs epo + PAD (3x
300 U/kg) n=11 vs
placebo + PAD n=10
RCT radical hysterectomy
PAD + epo (n=15) vs PAD
epo (n=15)
Aksoy 2001
A2
A2
RCT.
None
none
Epo + PAD vs
PAD
Other
Post
kidney
transplant
Van Biesen 2005
Post
kidney
337
transplant
Epo (100 IU/kg, 3 x week
to Hb 12.5 g/dL) (n =22)
vs control (n=18)
Baltar 2007
66.5 days
- No difference after 3
months
- Not efficient from cost
point of view.
- Hb correction in 86%.
Graft
survival:
71%
benefited from epo; no
graft
survival:
50%
benefited from epo.
- Epo had no effect on
renal function.
Post-operative anaemia
Karkouti 2006
A2
Ferraro 2004
- No significant reduction
in anaemia
- Hb pre-op 14.9 vs
12.9 g/dL
- Hb day 1 post-op: 11.7
vs 9.6 g/dL
- BT: 0 vs 1.6 units
(average)
Conclusions 8.1.3.5
Pre-operative therapy with EPO increases both the number of autologous
donations for collection in the case of pre-operative autologous blood
donation (PABD) and the peri-operative Hb.
Level 1
A1
A2
Laupacis 1998
Bovy 2006
338
Laupacis 1998
Moonen 2008, Weber 2005
Karkouti 2005
Level 1
Level 1
Administration of EPO for colorectal surgery does not reduce the number
of allogeneic blood transfusions. There are indications that this is the case
for prostatectomy, radical hysterectomy, plastic surgery and kidney
transplants.
A1
A2
Devon 2008
Dousias 2005, Baltar 2007
Recommendations 8.1.3.5
1.
2.
3.
4.
339
normal blood clotting, routine use of rFVIIa in the peri-operative phase was possibly
associated with an increase of thrombo-embolic complications (Johansson 2008).
A transfusion protocol was described in nine of the 17 studies, but three of these only
provided guidelines for the transfusion of erythrocytes. With the exception of one study,
traditional parameters were mainly used for the transfusion of plasma and platelets. Another
point of comment is that there was a difference in the platelet transfusion trigger. However,
conditions for an optimal effect of rFVIIa are a sufficient number of platelets and an adequate
fibrinogen level (Boffard 2005).
rFVIIa has a role as a rescue medication in the treatment of massive blood loss (see
Chapter 5), if all other conditions have been met and if there are sufficient opportunities
present to form a clot (platelets > 100 x 10 9/L and fibrinogen > 1.0 g/L). The optimum dose
for this indication is not known. A low dose (20 90 g/kg) appears to be effective (Vincent
2006). European guidelines (ESA and ESICM) recommend a dose of 200 g/kg, followed by
100 g/kg at 1 and 3 hours after the trauma. If the administered dose is effective, the dose
can be repeated once. If administration has not resulted in an effect, there is no point in
administering a second dose.
Table 8.1.3.6: Results of RCTs concerning rFVIIa for various indications
Author
Search
Results BT
Side effects
Level
Johansson 2008
BT = blood transfusion
BL = blood loss
TE = thrombo-embolism
ATE:
arterial
thrombotic
complications
TE 3. 1 in each rFVIIa group
A1
Intra-cerebral
haemorrhage
Dengue Fever
Cirrhosis
Prostatectomy
Liver transplant
N = 172 + 82. no
difference
Liver resection
N = 185 + 221. no
difference
Cardiovascular surgery
N = 20. no difference
Congenital
surgery
Burn wounds
N = 76. no difference
Spinal
N = 36. No difference
in blood loss. BL in
control
group
extremely high.
N = 48. no difference
Pelvic trauma
340
N = 100, 73 rFVIIa. No
difference
2 studies;
N = 48 + 399
Reduction haematoma
N = 25, 16 rFVIIa. No
difference
N = 245, no difference
heart
column
N = 18 50% fewer BT
in rFVIIa group
N = 49. Less BL
TE:
27/172 and 12/48
evenly distributed over both
groups
TE:
9 / 185 and 2 / 221
evenly distributed over both
groups
4 / 20
evenly distributed over both
groups
surgeries
Trauma
Blunt: N = 143
Sharp: N = 134
Initially no difference.
Planned after
48 hours post hoc
blunt: 2 6 U less.
Mayer also showed in a RCT that the outcome did not improve despite a decrease in intracerebral haematoma.
Conclusions 8.1.3.6
The use of recombinant factor VIIa (rFVIIa) in patients with bleeding
resulted in a decrease in the bleeding, but was associated with a significant
Level 1
increase in arterial and venous thrombo-embolic complications.
A1
Level 1
Johansson 2008
Other considerations
There are indications that the use of rFVIIa at a low dose can limit the blood loss due to blunt
trauma and that it could play a role as rescue medication in the case of major blood loss.
This only applies if abnormal coagulation has been corrected, the platelet count is > 100 x
109/L, the fibrinogen level > 1.0 g/L, and acidosis and hypothermia have been corrected.
More research is desirable, as is the implementation of national registration of rFVIIa use for
non-registered indications.
Recommendations 8.1.3.6
1.
One can consider using recombinant factor VIIa (rFVIIa) as rescue medication for
massive blood loss, provided the platelet count is > 100 x 10 9/L and the fibrinogen
level is > 1.0 g/L, and any acidosis and hypothermia have been corrected.
2.
The recommended dose of recombinant factor VIIa (rFVIIa) as rescue medication for
recommendation 1 is 90 120 g/kg. The administration may be repeated once if an
effect is observed.
3.
If no effect is seen after administration of recombinant factor VIIa (rFVIIa) as resuce
medication as mentioned under recommendation 1, repeat administration is not
recommended.
4.
In the case of off-label use of recombinant factor VIIa (rFVIIa is not authorised as a
rescue medication), the patient must be closely monitored for the occurrence of
thrombo-embolic complications.
341
8.1.4 Haemodilution
(Intentional) haemodilution is defined as the artificial reduction of the erythrocyte count in the
blood by dilution with crystalline or colloidal fluids. The treatment is aimed at reducing blood
loss.
ultrasound Doppler or via cardiac output monitoring (Suttner 2001, Jamnicki 2003, Licker
2004, Licker 2004). ANH can also result in an extension of the neuro-muscular block when
using rocuronium, but not with cisatracurium (Dahaba 2006).
Dilution can cause the concentration of clotting factors to decrease. The use of large
quantities of plasma expanders can cause coagulopathy, not only related to the effect of
dilution but also dependent on the component used (Levi 2007). Recent research has
demonstrated that in the case of infusion of colloids according to a protocol, this aspect is
less important (Hobisch-Hagen 1999, Ickx 2003, Jalali 2008). The coagulopathy .due to
plasma expanders was not observed . with the use of ANH during partial liver resections
(Matot 2002). Measurements of the plasma volume and erythrocyte volume using advanced
techniques have shown that a part of the infused plasma substitute or the protein solution
used disappears into the endothelial surface plasma layer (Glycocalix) and another part
leaves the circulation. This explains the fact that approximately 15% more plasma substitute
is required to replace the collected volume of blood (Rehm 2001, Jacob 2005). See also
table 8.1.4.2.
ANH is a cheap and easy technique to apply (Haynes 2002, Davies 2006).
Contra-indications of ANH
The contra-indications for the application of ANH are: pre-operative anaemia, sepsis, heart
failure or ischaemic heart disease, myocardial infarction, cardiogenic shock and severe
pulmonary disease. .Licker 2005).
8.1.4.2 Hypervolemic haemodilution (HVH)
In the case of hypervolemic haemodilution (HVH), the haematocrit is artificially reduced by
infusion of plasma substitutes/crystalloids to increase the circulating volume. Very little
research is available on this topic. One study shows a comparable result for HVH and ANH.
Singbartl and Saricaoglu recently demonstrated that HVH can be used as an alternative
blood-saving technique for patients who lose less than 40% of their circulating volume; ANH
is preferable if greater blood loss is expected (Saricaoglu 2005, Singbartl 2000).
Table 8.1.4.1: Efficacy of acute normovolemic haemodilution (ANH)
First author
Study set-up
Result
Evidence
class
General
Bryson 1998
Carless 2004
Orthopaedics
343
Olsfanger 1997
Saricaoglu 2005
Bennett J 2006
RCT TKP
ANH to Ht = 28 30% vs
none.
In ANH group, randomised
to 2 or 6 hour post-operative
re-infusion of autologous
blood
(n = 30)
RCT THP
ANH + 6% HES (10) vs
HHD + HES (n=10) vs
control (N=10)
RCT Ortho THP ANH (n=78)
vs Control (n=77)
BT trigger: Hb < 8 g/dL
21 units PC vs 5 7 in ANH A2
group. No difference if ANH
blood is returned 2 or 6 hours
post-operative.
(p < 0.024)
BT 20 vs 40 vs 100%
A2
19 vs 29% BT n.s.; 33 vs 63 EC A2
n.s.
OR 0.60 (p = 0.23)
Complications: 18 vs 38% (p =
0.009)
(Cardio)Vascular surgery
Kahraman 1997
Hhn 2002
McGill 2002
Ramnath 2003
RCT CABG
ANH 500 mL vs 1,000 mL vs
none (n = 42)
RCT CABG ANH + CS +
aprotinin (n=40) vs CS +
aprotinin (n=40)
RCT Cardiac surgery
CS (n=75) vs CS + ANH
(n=74) vs control (N=88)
RCT CABG
ANH (in heparin) (n=50) vs
ANH (in citrate) (n=48) vs
control (n=46)
A2
No difference in saving BT
So ANH no added benefit
A2
BT: 26 vs 43 patients
EC: average 0.68 vs 1.07/pp
ANH no added benefit
no saving in BT
A2
No difference in BT
Inflammatory response the same
A2
EC 17 vs 46
FFP 10 vs 47
No difference
parameters
B
in
A2
coagulation
Cardio 2006
Platelet
function
better
ANH in citrate (n=14) vs heparinised collected blood
ANH after heparinisation
(n=13)
in A2
Other surgery
Hans 2000
craniosynostosis
children No difference in BT
ANH to Ht 0.25 vs none
(n = 34)
Suttner 2001
RCT prostatectomy
BT effect ANH + CH equal to A2
Controlled Hypotension + ANH alone.
ANH (n=14) vs ANH (n=14) EC: 2 vs 2 vs 7 units
344
A2
Matot 2002
Ickx 2003
Sanders 2004
Jarnagin 2008
vs control (n=14)
RCT liver lobe resection
BT: 10 vs 36%
ANH (n=39) vs control No side effects
(n=39).
BT trigger: Ht = 0.20
L/L
RCT abdominal
ANH + HES 130/0.4 (n=20)
vs ANH + HES 200/0.5
(n=20)
RCT:
gastro-intestinal
surgery
ANH: 3 units (n=78) vs
control (n=82)
A2
A2
ANH:
increase
in
median A2
anaesthesia time 55 vs 40
minutes
Oliguria: 47 vs 67%
BT: no difference
RCT liver lobe resection ( 3 EC total: 12.7 vs 25.4%
A2
segments)
EC intra-op: 1.16 vs 10.4%
ANH (n=63) vs control BL > 800 ml:
(n=67)
FFP: 21.1 vs 48.3%
BT trigger < 8 gdL
Licker 2004
Licker 2004
Licker 2005
Dahaba 2006
Dahaba 2006
cervical cancer
345
Licker 2007
Dahaba 2008
RCT
ANH + BIS + extra O2
(n=15)
ANH + BIS + air (n=15)
Control (n=15)
All TCI propofol
Evidence
class
Orthopaedics
Oishi 1997
RCT. THP
% PAD blood that was used:
Gr 1 ANH + PAD + Cell Saving Grade 1: 41%
(CS)
Grade 2: 75% (p < 0.05)
Gr 2 PAD + CS
(n = 33)
Xenakis 1997
RCT, THP and TKP
Allogeneic BT
Group 1 CS
Group 1 2.7 U (No p value)
Group 2 CS + PAD
Groep 2 1.7 U
Group 3 control
Groep 3 4.2 U
(n = 208)
Goodnough 1999
RCT THP
No difference in BT between
both groups (p = 0.45)
PAD vs ANH TOT 28%
(n = 32)
Goodnough 2000
RCT THP
No difference in BT between
both groups (p = 0.30)
PAD vs ANH TOT 28%
(n = 48)
Gombotz 2000
RCT THP
Allogeneic BT required: group
1 group 2 group 3: 6 4
8 patients (ns)
Group 1 EPO
Group 2 EPO + ANH
Group 3 PAD
(n = 60)
A2
A2
A2
A2
A2
Urology
Boldt 1999
346
RCT, prostatectomy
Group 1 = ANH
Monk 1999
Conclusions 8.1.4
Acute normovolemic haemodilution (ANH) is a safe and cheap technique
that can save on allogeneic blood transfusions, if the expected blood loss
is at least 40% of the circulating volume. The efficacy increases with
Level 1
increasing pre-operative Hb.
A1
A2
Level 2
Saricaoglu 2005
Singbartl 2000
Other considerations
ANH is a technique that is easy to apply. In order to achieve an optimum effect, one should
realise that fresh blood is collected, which contains clotting factors and platelets. In order to
maintain platelet function, the collected blood should be stored at room temperature ..
If the blood is kept near the patient in the operating room, there is very little chance of a mixup. The collected blood is not tested for various blood-transmissible infections and
appropriate precautionary measures should be taken, including measures to protect the
(para) medical staff present in the operating room (The Society of Thoracic Surgeons and
The Society of Cardiovascular Anesthesiologists 2007).
As with ANH, the contra-indications for HVH in non-cardiac surgical procedures are: preoperative anaemia, sepsis, heart failure or ischaemic heart disease and severe pulmonary
disease.
These contra-indications also apply to cardiac surgery procedures. HVH is also contraindicated in cardiac surgical procedures if the patient has unstable symptoms or an acute
myocardial infarction, or is in cardiogenic shock. Complications of HVH can include:
pulmonary oedema and heart failure (expert opinion).
In ANH, the collected blood is not tested for blood-transmissible micro-organisms.
347
Recommendations 8.1.4
1.
2.
3.
4.
5.
6.
7.
8.2
348
paragraph 8.1.3.5), the number of units that can be collected . increases and the Hb
immediately before surgery is higher (see tables 8.2.1 and 8.2.2) (Bovy 2006, Hyllner 2002,
Hyllner 2005, Aksoy 2001, Bouchard 2008). A good indication . and good logistic procedures
are important (Freedman 2008, Dietrich 2005). Often, not all the units are returned. It is
estimated that roughly 25% of the units are not used and that on the other hand 25% of
patients require an allogeneic blood transfusion after all (Henry 2008). Recent research
reveals an even greater waste for total knee arthroplasty: only 11.3% of the collected units
were transfused and 1.9% received an allogeneic blood transfusion (Regis 2008).
There are insufficient data known to be able to draw conclusions about the effect of PAD on
mortality, infections, CVA, thrombosis or pulmonary emboli. A PAD donor receives relatively
more blood transfusions (autologous and allogeneic, but mostly autologous), often due to a
broader indication setting, thereby increasing the risks, for example the risk of a mix-up
(Henry 2008, Carless 2004).
On the other hand, there are indications that the number of infectious complications are less
with PAD than with allogeneic transfusions (Heiss 1997, Innherhof 2005).
PAD can also be indicated in the treatment of high risk patients, such as:
- in situations where compatible donor blood is not or hardly available;
- in the case of a previously demonstrated haemolytic transfusion reaction without a clear
cause.
See also Chapter 2
An alternative to pre-operative autologous blood donation (PAD) is a pre-operative
erythrocyte apheresis (Rubens 1998, Shulman 1998).
Table 8.2.1: Efficiency of pre-operative autologous blood donation (PAD) as a blood
transfusion saving technique
First author Study set-up
Result
Evidence
class
Forgie 1998
Carless
2004
Henry
CD 003602
349
Bouchard
2008
PAD
ANH
vs
Goodnough
2000
RCT ortho
Ht pre-op 39.7 vs 41.8% n.s.
PAD 3 U (n=25) vs ANH 3 U or BT 0 vs 17% p = 0.30
Ht = 0.28 (n=23)
ANH cheaper
A2
Table 8.2.2: Combination pre-operative autologous blood donation (PAD) with epoietin (EPO)
First author Study set-up
Result
Evidence class
Bovy 2006
Hyllner 2005
Hyllner 2002
Aksoy 2001
A2
Orthopaedic,
prospective
observational
PAD (n=85) vs leukoreduction
allogeneic (n=100) vs no BT
(n=101)
B2
A2
A2
A2
Other
Innerhof
2005
Infections:
1.2 vs 12 vs 6.9%
Allogeneic BT predictive infection:
OR 23.65
First
350
Study set-up
Result
Evidence
author
class
A1
Rubens
Meta-analysis
apheresis
of Blood loss:
Open heart platelet-rich plasma through to Group 1 102 mL < group 1 (p <
surgery
Aug. 1997
0.0001)
17 articles:
Group 0.33 U PC < group 2 (p <
Group 1 apheresis (n = 694)
0.0001)
Group 2 control (n = 675)
Effect greater in studies of marginal
quality (OR = 0.33) than in studies
with optimal study set-up (OR =
0.83)!!
2
Shulman
Group
1
Haemapheresis: Group 1: 0.7 allogeneic erythrocyte A2
Spondylodes platelet-rich
plasma
and concentrates/patient (p < 0.001)
is
erythrocytes + CS
0.3 U allogeneic FFP/patient (p <
Group 2 CS
0.05)
Transfusion trigger Ht = 24%
0 platelet concentrate
(n = 160)
Group 2: 3.2 allogeneic PC/patient
1.6 U allogeneic FFP/patient
24 platelet concentrate (total)
Admission duration in group 1 was
23% shorter than in group 2
(6.3 vs 8.4 days p < 0.04)
Conclusions 8.2.1
It is likely that the use of pre-operative autologous blood donation (PAD)
reduces the number of allogeneic units administered by 64%.
Level 2
A2
Level 2
Level 1
Level 3
Level 1
Carless 2004
There are indications that the number of infectious complications are less
with PAD than with allogeneic transfusions.
351
Level 1
A1
B
C
Rubens 1998
Shulman 1998
Other considerations
PAD is an efficient way of saving on allogeneic blood transfusions, provided there is a good
indication setting. For an optimal effect, a transfusion trigger comparable to that used for
allogeneic blood transfusions should be adhered to. Due to the more complex logistics of
PAD and the fact that the collected plasma normally is not used, the technique is more
expensive and no more safe (also documented by TRIP: see annual reports) than .
allogeneic blood transfusions and also results in the wasting of plasma.
Recommendations 8.2.1
1.
2.
3.
4.
5.
352
6.
The blood group / rhesus factor must be determined for each pre-operative
autologous blood donation (PAD) unit. Checks before transfusion are according to
the rules that apply to an allogeneic blood transfusion.
353
354
In general, all operations associated with significant blood loss form an indication for perioperative auto-transfusion. The benefit of the various types of auto-transfusion with respect
to the reduction in allogeneic transfusion depends on the type of surgery. Known indication
areas include cardiac surgery procedures, vascular surgery, orthopaedic surgery, liver
surgery, trauma surgery and surgical procedures in Jehovahs Witnesses. (see also
addendum 3 to Chapter 8).
Applications
Cardiac surgery
Re-infusion of the blood evacuated during surgery and the drain blood lost post-operatively
is an efficient way of saving on donor blood (Ferrari 2007, Klein 2008). The use of a
technique involving washing appears to be more efficient than a technique without washing
(RR washed units transfused = 0.61 versus unwashed = 0.87) (Hut 1999, Carless 2006).
Drain blood re-infusion is used a lot in cardiac surgery.
It has been shown that this blood, if re-infused without washing:
results in more cognitive dysfunction (15% versus 6% (Djaiani 2007));
causes haemodynamic instability, probably due to infusion of cytokines (Marcheix,
Boodwhani 2008);
causes complement activation (Marcheix, Boodwhani 2008);
can disrupt function tests, for example to demonstrate a myocardial infarction (Pleym
2005);
gives laboratory abnormalities consistent with increased fibrinolysis or DIC (Krohn
2001, Sinardi 2005). These are usually without clinical relevance (Krohn 2001,
Sinardi 2005), but some authors have demonstrated an increase in post-operative
blood loss (Schnbergen 1992, Wiefferink 2007). Other authors are unable to confirm
this (Schroeder 2007, Sirvinskas 2007).
Washing of the collected blood, which significantly reduces these complications, must
definitely be performed if the blood is suctioned peri-operatively (Carrier 2006, Westerberg
2005, Djaiani 2007, Svenmarker 2004).
Orthopaedics
Re-infusion of peri-operatively suctioned washed blood and (un)washed blood lost postoperatively was shown in most studies to be an efficient way of saving on donor blood (Hut
1999,Tylman 2001, Jones 2004, Carless 2006, Tsumara 2006, Smith 2007, Zacharopoulos
2007, Amin 2008, Tripkovic 2008; Muoz 2010, see table 8.2.2.2).
Approximatley 75% of post-operative blood loss takes place in the first 6 hours postoperative. (Wood 2008). This corresponds to the time normally maintained for the interval in
which drain blood can be re-infused. There are indications that a 6-hour period results in
better wound healing than when a longer period is maintained (Wood 2008). The Hb of the
collected drain blood is around 5 mmol/L.
According to some (So-Osman 2006, Kirkos 2006, Hendrych 2006), re-infusion of the
unwashed blood causes a mild febrile reaction, although other authors cannot confirm this
(Moonen 2008). This febrile reaction may depend on an increase in the IL-6 concentration.
Blood Transfusion Guideline, 2011
355
This concentration is elevated in collected blood in the first 6 hours and even increases 7fold over the next 6-hour period (Handel 2006). Filtration of the unwashed blood over a
leukocyte filter reduces the quantity of interleukins (IL-8 and TNF-), but causes
complement activation (Dalen 1998).
Re-infusion of unwashed blood does not alter lung perfusion (Altinel 2007). A slight decrease
in the platelet count does occur (de Jong 2007).
A study of 120 patients undergoing orthopaedic prosthetic surgery looked at the
immunological response to: no blood transfusion (BT), BT (non-leukocyte reduced), BT
(leukocyte reduced), PAD blood and unwashed auto-transfusion blood. The number of
Natural Killer (NK) cells and the interferon gamma level decreased due to surgery and blood
loss, except in the auto-transfusion group where the concentrations were higher. The IL-10
concentration remained the same. The higher concentration of interferon gamma could point
to improved immunity after re-infusion of unwashed drain blood (Gharehbaghian 2004).
Vascular surgery
Auto-transfusion of washed blood is used frequently during major vascular surgery. It is an
efficient method of reducing donor blood transfusions (RR 0.55) (Het 1999, Carless 2006).
Despite this, few randomised studies have been published, including Wong 2002, Takagi
2007; (see table 8.2.2.2).
Obstetrics
Auto-transfusion of washed blood is used during ectopic pregnancies and Caesarian
sections (Thomas 2005, Selo-Ojeme 2007). See also table 8.2.2.2.
The evacuated amniotic fluid contains substances that can cause DIC or amniotic fluid
emboli. It has been demonstrated that these harmful substances are removed by washing
(Thomas 2005). One has to realise that erythrocytes from the child can also be evacuated.
Re-infusion of erythrocytes from the child can promote antibody formation in the mother.
Most Caesarian sections result in very little blood loss, so that routine use is not indicated.
However, a cell saver can save lives in the case of major bleeding.
Urology
Auto-transfusion of washed blood is often used during radical cystectomies and
prostatectomies, without irradiation of the blood. Various studies have demonstrated that the
survival is the same as for surgical patients who did not receive auto-transfusion (Nieder
2004, 2007, Davis 2003, Ford 2007, Gallina 2007, Stoffel 2005, Waters 2004). PSAexpressing cells were demonstrated in the evacuated blood (Stoffel 2005). None of the
studies were randomised.
Traumatology
Auto-transfusion of washed blood is often used in traumatology. Especially in the case of
hepatic or splenic ruptures. No randomised studies have been published as yet.
In general, a bowel perforation forms a relative contra-indication. A recent randomised study
of patients with abdominal trauma with perforation of the bowel found that with the use of
auto-transfusion significantly fewer blood transfusions (6.47 U versus 11.17 U) were
356
required in the auto-transfusion group whilst there was no difference in morbidity and
mortality (Bowley 2006). All operations were performed under antibiotic prophylaxis. Blood
visibly contaminated by faecal matter was suctioned into a different container. This means
that auto-transfusion can be used under these conditions in emergencies (Bowley 2006).
Contra-indications
Contra-indications for peri-operative auto-transfusion are: rinsing with toxic substances,
locally used heamostatics, bacterial contamination (relative), tumour surgery (relative) and
sickle cell anaemia. Bacteria are not washed away completely (Thomas 1999). In
emergency situations, antibiotics can be given in the case of bacterial contamination.
In general, tumour surgery forms a contra-indication to auto-transfusion due to the risk of
haematogenic metastasis of tumour cells. Centrifugation and washing does not result in
removal of all tumour cells and results in less than 1 log reduction of the other cells
(Hanssen 2002, 2004, 2004, 2006, Thomas 1999, Stoffel 2005). See also table 8.2.2.4. The
tumour load in peri-operatively suctioned blood can be up to 10 7 cells per liter (Hanssen
2002, 2006). Leukocyte filtration results in 1 log reduction (Thomas 1999, Hanssen 2004,,
2006), but irradiation of washed blood with 50 Gy results in at least a 10 log reduction of the
number of viable tumour cells (Thomas 1999, Hansen 2002). A combination of leukocyte
filtration followed by irradiation effectively disables active tumour cells (Poli 2008).
Experiences of peri-operative auto-transfusion (including safety) have now been described
for over 700 oncological surgery procedures (Hanssen 2004, Valbonesi 1999).
Auto-transfusion can be life-saving during oncological surgery in Jehovahs Witnesses
(Nieder 2004). The patient must be consulted in advance to discuss the possible risks. If a
radiation unit is not available, a leukocyte filter should be used.
Table 8.2.2.1: Meta-analysis of auto-transfusion
Author
Study set-up
Results
Carless
Cochrane
001888
Metaanalysis
CD
Overall: RR = 0. 62
Ortho: RR = 0.46
Cardio: RR = 0.77
1966 2009
75 RCT, n=3857
Ortho: N = 36
Cardio: n= 33
Vasc: N = 6
60 with BT protocol
(of which 59 trigger):
- 55 post-operative,
-21
also
intraoperative
without
Mortality,
re-operation,
wound
infection,
thrombosis, stroke,
infarction, duration
of admission n.s.
Evidence
class
A1
Washed: N = 27
Unwashed: n = 40
Other: N = 8
15
Comments
BT
Infection:
trend
lower in auto-transf.
group RR 0.68, n.s.
(wound
infection
equal)
Any infection, nonfatal
myocardial
infarction in control
group, trend lower
in
auto-transf.
group (5.1 and
4.8%)
357
protocol
Without BT protocol:
0.56;
RR = Relative Risk of allogeneic blood transfusion
RR =
Evidence
class
Cardio:
Hut 1999
Meta-analysis
Unwashed;
12 RCT.
total 984 patients;
RR = 0.85
Svenmarker
2004
RCT
peri-operative
cardio CS (n = 30) vs
unwashed (n = 30)
protein S100B as
marked
of
brain
damage
and
3
memory tests
RCT cardio 2005
post-operative.
Unwashed (n = 23) vs
none (n = 24). 8
hours
Effect on biochemical
parameters,
myocardial damage
RCT peri-operatively
washed (n = 15) vs
unwashed (n = 15)
Immunological
consequences
Unwashed
significant
increase S100B (1.42 vs
0.25)
RCT
cardio
CS
(n=20) vs unwashed
(n=20)
RCT
peri-operative
Washed (n = 18) vs
unwashed (n = 19)
and
immunological
response
RCT
cardio
perioperative CS (n=112)
vs unwashed (n=114)
12-hour study of cog.
dysfuntion and emboli
A2
A2
BT EC and TC n.s.
FFP: 25 vs 12%
Cognitive
dysfunction
weeks p.o. 6 vs 15%
A2
Pleym 2005
Westerberg
2005
Carrier 2006
Allen 2007
Djaiani 2007
358
Reported in
11
studies
In 1 study median
of 750 mL, other
study average
< 400 mL
No
clinical
difference
demonstrated
in
memory tests
A1
A2
A2
Washing
reduces
the harmful vasoactive substances.
This is expressed in
more
stable
haemodynamics
A2
Sirvinskas 2007
RCT
cardio
unwashed (n=41) vs
control (n=49)
Wiefferink 2007
Marcheix 2008
No indications for
increase
in
complications,
on
the contrary
A2
A2
A2
Effects
on
immunology
All aprotinin
Klein 2008
RCT
Washed (n=102) vs
control (n=111)
A2
Boodhwani
2008
RCT
peri-operative
washed (n = 132) vs
unwashed (n = 134) +
haemodynamics
A2
Meta-analysis
Orthopaedics 16 RTs:
n= 478.
7 washed technique,
9
unwashed
technique
Prospective
n=81
TKP
IL-6
measurements
Orthopaedics
Hut1999
Handel 2001
In
10
studies,
protocol maximum
average
quantity
unwashed
blood
946 mL; all others <
average 700 mL
3 febrile reactions:
IL-6 11 ng/mL
A1
359
Unwashed, 6 + 6
hours (2 times reinfusion
with
the
same set)
Thereafter to 47 ng/mL
RCT
unwashed (n = 7) vs
washed (n = 7) vs no
BT
(BL < 400 ml)
interleukins
RCT unwashed with
leukocyte filter (n=11)
vs unwashed without
(n=12)
Immunology
Prospective
CT
unwashed (n=94) vs
control (n=92)
Unwashed (n=12) vs
no
(n=12).
Immunological
consequences
A2
A2
Unwashed (n=88) vs
control (n=44)
Trigger:
re-infusion
maximum 800 ml
BT 31 vs 100%
2% temp > 38.5
unwashed group
Kirkos 2006
RCT
unwashed
(n=78)
(sub
group
+
corticosteroids
53 vs not 25)
vs control (n=77).
BT EC:
Peri-op: 0 vs 0.57
Post-op: 0.54 vs 1.06 U
Fever: 50 vs 61%
In group unwashed + cort.
vs not: 47 vs 56%
So 2006
No difference in BT
Tylman 2001
Dalen 1999
Jones 2004
De Jong 2006
Hendrych 2006
360
Transfusion costs
similar 182.70 vs
196.75 pounds
A2
C in
Complications:
Allogeneic BT: 4 x
(1 x serum reaction,
2 x allergic reaction,
1 x embolism)
Auto-transfusion: 4
x
(3x clot, so no reinfusion possible;
1x haemolysis due
to too small drain)
30%
autotransfusion
group
mild febrile reaction
after infusion
A2 or B
(could not
be
determined
due
to
language)
A2
A2
Tsumara 2006
Abuzakuk 2007
Altinel 2007
Tripcovic 2008
Moonen 2007
Smith 2007
RCT
unwashed (n=76) vs
control (n=82)
Zacharopoulos
2007
Amin 2008
Wood 2008
RCT
unwashed (n=30) vs
control (n=30) BT
trigger < 9 g/dL or
symptoms
RCT
unwashed (n=92) vs
control (n=86)
RCT unwashed drain
removed 6 hours
post-op (n=40)
vs 24 hours (n=40)
BT trigger < 8 g/dL or
symptoms
none
No reduction BT
BT 300 vs 685 mL
No difference in
perfusion
A2
A2
A2
lung
BT 12 vs 80%
none
BT 6 vs 19%
TKP 2 vs 16% p = 0.04
A2
A2
A2
Expenses 36%
A2
No difference in BT
A2
BL no difference
75% of the BL takes place in
the first 6 hours
Allogeneic BT 17.5 vs 5%.
Volume of auto-transfusion
THP 250 ml, TKP 500 ml.
THP (15%) more BT than
TKP (7.5%) despite autotransfusion.
Hb equal in both groups.
6-hour group tended to have
better wound healing
A2
361
Vascular
surgery
Wong 2002
Takagi 2007
BT 43 vs 56%
None
RR 0.63
A2
A1
Obstetrics
Thomas 2005
Saver
not
necessary
during
routine Caesarian
EUG RCT
cs (n=56) vs
none (n=56)
by leukocyte filter
Ht 0.29 vs 0.26 L/L
With CS, 3x higher chance
of discharge Ht 0.27 L/L
Wixson 1994
RCT AAA:
washed (n = 6) vs
unwashed (n = 6) vs
control group: (n = 6)
healthy volunteers
Erythrocyte survival
Unwashed: 28 THP 22
TKP:
erythrocyte
survival (111In:51Cr ratio)
coagulation
abnormalities
Comments
No difference in survival
Evidence
class
A2
No difference in survival. No
clinical signs of DIC, despite
demonstrable increase in
clotting
breakdown
components and haemolysis
parameters
Wollinsky 1997
RCT
Surgical field and wound drain
blood no bact. Contamination.
Some suction tips did (6 vs 3).
TPH n=40
No AB prophylaxis Collection bag (8 vs 0)
Re-infusion bags (8 vs 3; 3 vs
(n=20) vs with (n=20)
0; 0 vs 0)
Low pathogenic
Krohn 2001
Orthopaedic
n=9 2-antiplasmin 31% of pre-op
clotting factors
value,
Plasmin-antiplasmin
concentration elevated, Ddimer elevated in collected
362
A2
Antibiotic
A2
prophylaxis reduces
contamination
of
suction tips and
collection bags.
Caution:
further C
bleeding due to
plasmin overload
Ramirez 2002
Reijngoud
2009
Vermeijden
2008
Hansen
Hansen34
Hansen
Valbonesi
Hansen36
Evidence
class
A1
363
First author
Study performed
Stoffel 2005
Analysis of blood
samples 112 CS
procedures with rad.
prostatectomy.
48 CS and 64 not
Nieder 2007
Waters 2008
Result
Comments
Autotransfusion
not related to
survival.
40
months
follow-up
RCT
abdominal
EC: 6.47 vs 11.17.
trauma
with
perforation.
CS Survival: 35 vs 33% n.s.
(n=21) vs control Bowel injury 85 vs 75%
(n=23)
All
antibiotic
prophylaxis
Grossly
contaminated
blood was not
suctioned.
Evidence
class
Contamination
Bowley 2006
Conclusions 8.2.2
Peri-operative auto-transfusion is a safe and effective technique to reduce
the transfusion of allogeneic blood varying from 33 to 58%, depending on
Level 1
the type of surgery.
A1
Level 1
Level 1
364
Carless 2006
Moonen 2008
Level 3
Level 3
Thomas 2005
Other considerations
Auto-transfusion of blood lost peri-operatively is the most commonly used blood saving
technique in the Netherlands. One advantage of this technique is that the blood can be
collected first and one can decide at a later stage whether it should be processed and/or
returned to the patient. This significantly reduces the costs.
In the Netherlands, the equipment is usually operated by anaesthesiology technicians or in
the case of post-operative use recovery room nurses / ward nurses which does not require
additional specialised personnel.
The safety of re-infusion of peri-operatively collected unwashed blood has not been
demonstrated or published in large series. Therefore, this can currently not be
recommended as a standard technique.
Recommendations 8.2.2
1.
2.
3.
4.
5.
365
6.
7.
8.3
The total yield increases with a combination of various blood saving techniques: see table
8.3. The number of units of pre-operative autologous blood donation (PAD) can be increased
by administering EPO injections (see also paragraph 8.2.1, table 8.2.2). Acute normovolemic
haemodilution (ANH) is also often combined with other techniques and medication (see also
paragraph 8.1.4, table 8.1.4.3). The preferred combination depends on the expected
quantity of blood loss, the initial Hb of the patient, the condition of the patient and the nature
of the procedure. For example, for an orthopaedic procedure the combination
EPO/PAD/tranexamic acid and peri-operative auto-transfusion is often used. For heart
operations, the combination of acute normovolemic haemodilution and peri-operative autotransfusion and tranexamic acid is often used. See table 8.3 for an overview of the studies in
this field.
For all combinations, the peri-operative transfusion trigger that is used largely determines
the expected yield (Weber 2000).
Table 8.3: Combination of techniques
First author
Study set-up
Tempe4
CABG
Group 1 ANH + CS
Group 2 ANH
Group 3 none
(n = 150)
Group 1: EPO/PAD
Group 2 Placebo/PAD
N = 173
Result
Evidence
class
366
A2
A2
A2
A2
A2
A2
prostatectomies
50
mmHg
nitroprusside
Group 3: control
N = 60
First author
Study set-up
with
Result
Evidence
class
Borghi10
Combination PAD and CS
89.9% PAD possible (2 3 U)
THP, TKP, primary Transfusion trigger: clinical or 82.3% intra-op CS (228 mL ave.)
and revision
Hb < 6 g/dL
96.7% post-op CS (421 mL ave.)
(n = 2.303)
92% no transfusion
11
Goodnough
PAD vs ANH TOT 28% No difference in BT between both
TKP
groups
(n = 32)
Vd Jagt12
Study group
Study of EPO, however combination
Target group
(n = 51- 43 and 48)
of techniques used
300 IU/kg vs 600 IU/kg vs 750 Not clear in study what the effect of
Hb 6.2 mmol/L
IU/kg; 2 injections + Fe oral
Hb < 8.2 mmol/L
this was on the results
Whether
2 Control group (n = 55)
injections
are Placebo + Fe oral
1x
auto-transfusion
perisufficient
operative; 8x haemodilution;
9x
auto-transfusion
postoperative
Monk13
Group 1 = PAD
No BT group 1 group 2 group 3
Radical
Group 2 = EPO + ANH
85 81 96%
prostatectomy
Group 3 = ANH + placebo
(n = 79)
Goodnough14
PAD vs ANH to 28%
No difference in BT between both
Prim THP
(n = 48)
groups
Gombotz15
Group 1 EPO
Allogeneic BT req. Group 1 group
Prim THP
Group 2 EPO + ANH
2
Group 3 PAD
group 3:
(n = 60)
6 4 8 patients (ns)
16
Aksoy
Group 1 PABD + EPO
PAD collected
TPH
Group 2 PABD+ placebo
group 1: 48 U
(n = 40)
group 2: 49 U
Allogeneic transfusions
Group 1 7 U
Group 2 13 U
Stover17
Group 1
epsilon
amino Group 1
Open heart surgery hexanoic acid + platelet rich 0% platelet concentrate (p < 0.01)
plasma
31% PC = 0.7 U/pat (p = 0.35)
Group 2
epsilon
amino Group 2
hexanoic acid
28% platelet concentrate
(n = 55)
45% erythrocyte concentrate =
1.2 U/patient
Suttner18
A2
group
1:
Na
A2
A2
A2
A2
A2
A2
A2
367
mean 50 mmHg
group 2: Na-nitro + ANH
group 3: standard
(n = 42)
Radical
prostatectomies
group 1: 788 ml
group 2: 861 ml
group 3: 1,355 ml
Allogeneic PC
group 1: 3 units
group 2: 2 units
group 3: 17 units
Conclusions 8.3
Level 1
Level 3
Weber 2000
Other considerations
Each technique has its own contribution to prevent allogeneic blood transfusion. By using
each specific effect and by careful planning, it is possible to compensate for blood loss over
5 litres without a single allogeneic blood transfusion.
For an optimal yield, it is important to determine a strategy in advance, which takes into
account the nature of the procedure, the Hb and the expected blood loss.
The working group is of the opinion that a specific recommendation per procedure would
exceed the scope of the Blood Transfusion Guideline.
Recommendations 8.3
1.
Where possible, use a combination of techniques to reduce the number of allogeneic
blood transfusions.
2.
For an optimal yield of any combination of blood saving techniques and medications
for surgical procedures, it is recommended to determine a strategy beforehand,
which takes into consideration the nature of the procedure, the Hb and the expected
blood loss.
Literature Introduction
1.
Literature 8.1.1
1.
368
Agolini SF, Shah K, Jaffe J, Newcomb J, Rhodes M, Reed JF 3rd. Arterial embolization is a
rapid and effective technique for controlling pelvic fracture hemorrhage. J Trauma
1997l;43:395-9.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Baer HU, Stain SC, Guastella T, Maddern GJ, Blumgart LH. Hepatic resection using a water
jet dissector. HPB Surg 1993;6:189-98.
Beard NA, Beard CR, Camprubi A. Alternative techniques and treatments to transfusion.
Second of two parts. Literature review. Arch Surg 1999;143:1-14.
Beekley AC. Damage control resuscitation: a sensible approach to the exsanguinating
surgical patient. Crit Care med 2008; 36: S26774.
Ben-Menachem Y, Coldwell DM, Young JW, Burgess AR. Hemorrhage associated with pelvic
fractures: causes, diagnosis, and emergent management. Am J Roentgenol 1991;157:100514.
Berde CB, Strichartz GR. Local anesthetics. In: Miller RD (ed). Anesthesia. 5th edition. New
York: Churchill Livingstone, 2000. p. 491-521.
Caprotti R, Porta G, Franciosi C, Codecasa G, Romano F, Musco F, et al. Laparoscopic
splenectomy for hematological disorders. Our experience in adult and pediatric patients. Int
Surg 1998;83:303-7.
Clinical strategies for avoiding and controlling hemorrhage and anemia without blood
transfusion in surgical patients. In: brochure distributed by hospital information services for
Jehovahs witnesses. New York, 2001.
Cohn SM, Cross JH, Ivy ME, Feinstein AJ, Samotowka MA. Fibrin glue terminates massive
bleeding after complex hepatic injury. J Trauma 1998;45:666-72.
Cornford PA, Biyani CS, Brough SJ, Powell CS. Daycase transurethral incision of the prostate
using the holmium: YAG laser: initial experience. Br J Urol 1997;79:383-4.
Epstein MR, Mayer JE Jr, Duncan BW. Use of an ultrasonic scalpel as an alternative to
electrocautery in patients with pacemakers. Ann Thorac Surg 1998;65:1802-4.
Gombotz H, Metzler H, List WF. Methods for reduction of perioperative bleeding. Br J
Anaesth 1998;81(Suppl 1):62-6.
Hirshberg A, Mattox KL. Planned reoperation for severe trauma. Ann Surg 1995;222:3-8.
Hoenig DM, Chrostek CA, Amaral JF. Laparosonic coagulating shears: alternative method of
hemostatic control of unsupported tissue. J Endourol 1996;10:431-3.
Holting T, Buhr HJ, Richter GM, Roeren T, Friedl W, Herfarth C. Diagnosis and treatment of
retroperitoneal hematoma in multiple trauma patients. Arch Orthop Trauma Surg
1992;111:323-6.
Idowu O, Hayes-Jordan A. Partial splenectomy in children under 4 years of age with
hemoglobinopathy. J Pediatr Surg 1998;33:1251-3.
Kerbl K, Clayman RV. Acute hemostasis during laparoscopic procedures: method for
intraoperative application of hemostatic material. J Urol 1994;151:109-10.
Kram HB, Shoemaker WC, Clark SR, Macabee JR, Yamaguchi MA. Spraying of aerosolized
fibrin glue in the treatment of nonsuturable hemorrhage. Am Surg 1991;57:381-4.
Kuster GG, Fischer B. Pharmacologic hemostasis in laparoscopy: topical epinephrine
facilitates cholecystectomy. Am Surg 1993;59:281-4.
McCarthy PM. Fibrin glue in cardiothoracic surgery. Transfus Med Rev 1993;7:173-9.
McCormick PA, Dick R, Burrooughs AK. Review article: the transjugular intrahepatic
portosystemic shunt (TIPS) in the treatment of portal hypertension. Aliment Pharmacol Ther
1994;8:273-82.
OReilly MJ, Saye WB, Mullins SG, Pinto SE, Falkner PT. Technique of hand-assisted
laparoscopic surgery. J Laparoendosc Surg 1996;6:239-44.
Ochsner MG. Fibrin solutions to control hemorrhage in the trauma patint. J Long Term Eff
Med Implants 1998;8:161-73.
Orloff MJ, Bell RH Jr, Orloff MS, Hardison WG, Greenburg AG. Prospective randomized trial
of emergency portacaval shunt and emergency medical therapy in unselected cirrhotic
patients with bleeding varices. Hepatology 1994;20(4 Pt 1):863-72.
Ragde H, Elgamal AA, Snow PB, Brandt J, Bartolucci AA, Nadir BS, et al. Ten-year disease
free survival after transperineal sonography-guided iodine125 brachytherapy with or without
45-gray external beam irradiation in the treatment of patients with clinically localized, low to
high Gleason grade prostate carcinoma. Cancer 1998;83:989-1001.
369
26.
27.
28.
29.
30.
31.
32.
33.
34.
Rau HG, Meyer G, Cohnert TU, Schardey HM, Jauch K, Schildberg FW. Laparoscopic liver
resection with the water-jet dissector. Surg Endosc 1995;9:1009-12.
Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: evolution of
technique towards bloodless surgery. Br J Surg 1996;83:1526-9.
Riegle EV, Gunter JB, Lusk RP, Muntz HR, Weiss KL. Comparison of vasoconstrictors for
functional endoscopic sinus surgery in children. Laryngoscope 1992;102:820-3.
Ross JH, Kay R, Alexander F. Management of bilateral Wilms tumors in the daughter of
Jehovahs Witnesses. J Pediatr Surg 1997;32:1759-60.
Sheridan RL, Szyfelbein SK. Staged high-dose epinephrine clysis is safe and effective in
extensive tangential burn excisions in children. Burns 1999;25:745-8.
Spahn DR e.a. Management of bleeding following major trauma: a European guideline. Crit
Care 2007; 11: R17
Willmann JK, Roos JE, Platz A, Pfammatter T, Hilfiker PR, Marincek B, et al. Multidetector
CT: detection of active hemorrage in patients with blunt abdominal trauma. Am J Roentgenol
2002;179:437-44.
Wu CC, Yang MD, Liu TJ. Improvements in hepatocellular carcinoma resection by
intraoperative ultrasonography and intermittent hepatic inflow blood occlusion. Jpn J Clin
Oncol 1992;22:107-12.
Wyman A, Rogers K. Randomized trial of laser scalpel for modified radical mastectomy. Br J
Surg 1993;80:871-3.
Literature 8.1.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
370
15.
Suttner SW, Piper SN, Lang K, Huttner I, Kumle B, Boldt J. Cerebral effects and blood
sparing efficiency of sodium nitroprusside-induced hypotension alone and in combination with
acute normovolemic haemodilution. Br J Anasth 2001;87:699-705.
Literature 8.1.3.2
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Bongers MY, Mol BW, Brlmann HA.Current treatment of dysfunctional uterine bleeding.
Maturitas. 2004 Mar 15;47(3):159-74.
Brown JR, Birkmeyer NJO and Oonnor GT. Meta-analysis comparing the effectiveness and
adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007; 115: 28012813.
Caglar GS, Tasci Y, Kayikcioglu F, Haberal A. Intravenous tranexamic acid use in
myomectomy: a prospective randomized double-blind placebo controlled study. Eur J Obstet
Gynecol Reprod Biol. 2008 Apr;137(2):227-31.
Carley S, Sen A. Best evidence topic report. Antifibrinolytics for the initial management of
subarachnoid haemorrhage. Emerg Med J. 2005 Apr;22(4):274-5.
Duckitt K. Medical management of perimenopausal menorrhagia: an evidence-based
approach. Menopause Int. 2007 Mar;13(1):14-8.
Dunn CJ, Goa KL. Tranexamic Acid. A review of its use in surgery and other indications.
Drugs 1999;57:1005-32.
Engel JM, Hohaus T, Ruwoldt R, Menges T, Jurgensen I, Hempelmann G. Regional
hemostatic status and blood requirements after total knee arthroplasty with and without
tranexamic acid or aprotinin. Anesth Analg 2001;92:775-80.
Faught C, Wells P, Fergusson D and Laupacis A. Adverse effects of methods for minimizing
perioperatiev allogeneic transfusion: a critical review of the literature. Transf Medicine
Reviews 1998; 12 (3): 206-225.
Fergusson DA, Hbert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM et. al.. A
comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med.
2008 May 29;358(22):2319-31.
Fraser IS, Porte RJ, Kouides PA, Lukes AS. A benefit-risk review of systemic haemostatic
agents: part 2: in excessive or heavy menstrual bleeding. Drug Saf. 2008;31(4):275-82.
Fraser IS, Porte RJ, Kouides PA, Lukes AS. A benefit-risk review of systemic haemostatic
agents: part 1: in major surgery. Drug Saf. 2008;31(3):217-30.
Gai MY, Wu LF, Su QF, Tatsumoto K. Clinical observation of blood loss reduced by
tranexamic acid during and after caesarian section: a multi-center, randomized trial. Eur J
Obstet Gynecol Reprod Biol. 2004 Feb 10;112(2):154-7.
Gluud LL, Klingenberg SL, Langholz SE. Systematic review: tranexamic acid for upper
gastrointestinal bleeding. Aliment Pharmacol Ther. 2008 May;27(9):752-8.
Gluud LL, Klingenberg SL, Langholz E. Tranexamic acid for upper gastrointestinal bleeding.
(Protocol) Cochrane Database of Systematic. Reviews 2007, Issue 3. Art. No.: CD006640.
DOI: 10.1002/14651858.CD006640.
Groenland THN and Porte RJ.Antifibrinolytics in liver transplantation. Int Anesthesiol Clinics
2006; 44(3): 83-97.
Henry DA, OConnell DL. Effects of fibrinolytic inhibitors on mortality from upper
gastrointestinal haemorrhage. BMJ 1989; 298: 1142-6.
Henry DA, Carless PA, Moxey AJ, OConnell D, Stokes BJ, McClelland B, Laupacis A,
Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.
Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001886. DOI:
10.1002/14651858.CD001886.pub2.
Jimenez JJ, Iribarren JL, Lorente L, Rodriguez JM, Hernandez D, Nassar I et al.. Tranexamic
acid attenuates inflammatory response in cardiopulmonary bypass surgery trhough blockade
if fibrinolysis: a case control study followed by a randomized double-blinded controlled trial.
Crit Care 2007; 11 (6): R117
Kadir RA, Chi C. Women and von Willebrand disease: controversies in diagnosis and
management. Semin Thromb Hemost. 2006 Sep;32(6):605-15.
371
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Kang HM, Kalnoski MH, Frederick M and Chandler WL. The kinetics of plasmin inhibition by
aprotinin in vivo. Thromb Res 2005; 115(4):327-40.
Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A et. al.. A
propensity score case-control comparison of aprotinin and tranexamic acid in hightransfusion-risk cardiac surgery. Transfusion 2006; 46: 327-338.
Kriplani A, Kulshrestha V, Agarwal N, Diwakar S. Role of tranexamic acid in management of
dysfunctional uterine bleeding in comparison with medroxyprogesterone acetate. J Obstet
Gynaecol. 2006 Oct;26(7):673-8.
Liu-DeRyke X, Rhoney D. Hemostatic therapy for the treatment of intracranial hemorrhage.
Pharmacotherapy. 2008 Apr;28(4):485-95.
Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D et. al.. Investigators of
The Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and
Education Foundation. Mortality associated with aprotinin during 5 years following coronary
artery bypass graft surgery. JAMA 2007; 7;297(5):471-9
Mangano DT, Tudor IC and Dietzel C. Multicenter Study of Perioperative Ischemia Research
Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in
cardiac surgery. N Engl J Med 2006; 26;354(4):353-65
Martin-Hirsch PL, Kitchener H. Interventions for preventing blood loss during the treatment of
cervical intraepithelial neoplasia. Cochrane Database of Systematic Reviews 1999, Issue 1.
Art. No.: CD001421. DOI: 10.1002/14651858.CD001421.
Molenaar IQ, Warnaar N, Groen H, Tenvergert EM, Slooff MJ, Porte RJ.Efficacy and safety of
antifibrinolytic drugs in liver transplantation: a systematic review and meta-anhalysis. Am J of
Transpl 2007; 7: 185-194
Phupong V, Sophonsritsuk A, Taneepanichskul S. The effect of tranexamic acid for treatment
of irregular uterine bleeding secondary to Norplant use. Contraception. 2006 Mar;73(3):253-6.
Roos YB, Rinkel GJE, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for
aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2003,
Issue 2. Art. No.: CD001245. DOI: 10.1002/14651858.CD001245. Cochrane Database of
Systematic Reviews, Issue 4, 2008
Selinger CP, Ang YS. Gastric antral vascular ectasia (GAVE): an update on clinical
presentation, pathophysiology and treatment. Digestion. 2008;77(2):131-7.
Umscheid CA, Kohl BA and Williams K. Antifibrinolytic use in adult cardiac surgery. Curr
Opinion Hematol 2007; 14(5): 455-67.
Literature 8.1.3.3
31.
32.
33.
34.
35.
36.
37.
372
Anonymous. Practice guidelines for perioperative blood transfusion and adjuvant therapies.
Anesthesiology 2006; 105: 198-208
Ferrari VA e.a. Perioperative blood transfusion and blood conservation in cardiac surgery: the
society of thoracic surgeons and the society of cardiovascular anesthesiologists clinical
practice guideline. Ann Thorac Surg 2007; 83: S27-86.
Henry DA, Mozey AJ, Carless PA, OConnell D, McClelland B, Henderson KW, et al.
Desmopressin for minimising perioperative allogeneic blood transfusions. Cochrane Database
Syst Rev 2001:CD001884.
Laupacis A, Fergusson D, ISPOT Investigators. Drugs to minimize perioperative blood loss in
cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth
Analg 1997;85:1258-67.
Levi M, Cromheecke ME, Jonge E de, Prins MH, Mol BJM de, Briet E, et al. Pharmacological
strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically
relevant endpoints. Lancet 1999;354:1940-7.
Oliver WC, Santrach PJ, Danielson GK, Nuttall GA, Schroeder DR. Desmopressin does not
reduce bleeding and transfusion requirement in heart operations. Ann Thorac Surg
2000;70:1923-30.
Ozkizacik E, Islamoglu F, Posacioglu H, Yagdi T, Basarir S, Omay SB. Desmopressin usage
in elective cardiac surgery. J Cardiovasc Surg (Torino) 2001;42:741-7.
Literature 8.1.3.4.1
1.
Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimising peri-operative
allogeneic blood transfusion. Cochrane Database of Systemic Reviews, 2010, issue 4, No CD
001888. DOI: 10.1002/14651858.CD001888.pub4
Literature 8.1.3.4.2
1.
2.
3.
4.
5.
6.
Chouhan VD, De La Cadena RA, Nagawani GC, Weisel JW, Kajani M, Rao AK. Simultaneous
occurrence of human antibodies directed against fibrinogen, thrombin and Factor V following
exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet
function. Thrombo Haemost 1997; 77:343-9.
Everts P, Devilee RJL, Brown Mahoney Ch, Eeftinck Schattenkerk, M, Box H, Knape, J, van
Zundert A. Platelet gel and fibrin sealant reduce allogenic blood transfusions and incidence of
infections in total knee arthroplasty. Acta Anaesth Scand 2006;50:593-9.
Everts PAM, Jakimowicz JJ, van Beek M, Schnberger JPAM ,Devilee RJJ, Overdevest EP,
Knape JTA , van Zundert A. Reviewing the structural features of autologous platelet-leukocyte
gel and suggestions for use in surgery. European Surgical Research 2007; 39:199-207
Ferrari M, Zia S, VAlbonesi M, Henriquet F, Venere G. Spagnolo S, Grasso M, Panzani I. A
new technique for hemodilution, preparation of autologous platelet-rich plasma and
intraoperative blood salvage in cardiac surgery. Int J Art Org 1987;10: 47-50
Marx RE. Platelet rich plasma (PRP): what is PRP and what is not PRP? Implant Dent
2001;10: 225-8
Rubens FD, Fergusson D, Wells PS, Huang M, McGowan J. Laupacis A. Platelet-rich
plasmapheresis in cardiac surgery: a meta-analysis of the effect on transfusion requirements.
J Thorac Cardiovasc Surg 1998; 116: 641-7
Literature 8.1.3.5
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
373
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Hardwick ME, Morris BM, Colwell CW Jr. Two-dose epoetin alfa reduces blood transfusions
compared with autologous donation. Clin Orthop Relat Res. 2004 Jun;(423):240-4.
Hyllner M, Avall A, Bengtson JP, Bengtsson A. IL-6 and IL-8 response to erythropoietin
therapy in radical hysterectomy. Acta Anaesthesiol Scand. 2005 Jan;49(1):47-51.
Iperen CE van, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, Wiel A van de.
Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in
intensive care unit patients. Crit Care Med 2000;28:2773-8.
Karkouti K, McCluskey SA, Evans L, Mahomed N, Ghannam M and Davey R. Erythropoietin
is an effective clinical modality for reducing RBC transfusion in joint surgery. Can J Anesth
2005; 52 (4): 362-368.
Keating EM, Callaghan JJ, Ranawat AS, Bhirangi K, Ranawat CS. A randomized, parallelgroup, open-label trial of recombinant human erythropoietin vs preoperative autologous
donation in primary total joint arthroplasty: effect on postoperative vigor and handgrip
strength. J Arthroplasty. 2007 Apr;22(3):325-33.
Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: a
systematic review of randomized trials. The International Study of Peri-operative Transfusion
(ISPOT) Investigators (A.W.M.M. Koopman-van Gemert for the Netherlands).Transfus Med.
1998 Dec;8(4):309-1.
Markham A, Bryson HM. Epoetin alfa. A review of its pharmacodynamic and pharmacokinetic
properties and therapeutic use in nonrenal applications. Drugs 1995;49:232-54.
Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P. Pre-operative
injections of epoetin-alpha versus post-operative retransfusion of autologous shed blood in
total hip and knee replacement: a prospective randomised clinical trial. J Bone Joint Surg Br.
2008 Aug;90(8):1079-83.
Muirhead N, Bargman J, Brugess E, Jindal KK, Levin A, Nolin L, et al. Evidence-based
recommendations for the clinical use of recombinant human erythropoietin. Am J Kidney Dis
1995;26(2 Suppl):S1-24.
Rosencher N, Poisson D, Albi A, Aperce M, Barr J, Samama CM. Two injections of
erythropoietin correct moderate anemia in most patients awaiting orthopedic surgery. Can J
Anaesth. 2005 Feb;52(2):160-5.
Weber EW, Slappendel R, Hmon Y, Mhler S, Daln T, Rouwet E, van Os J, Vosmaer A,
van der Ark P. Effects of epoetin alfa on blood transfusions and postoperative recovery in
orthopaedic surgery: the European Epoetin Alfa Surgery Trial (EEST). Eur J Anaesthesiol.
2005 Apr;22(4):249-57.
Weiss G and Goodnough L. Anemia of the chronic disease. NEJM 2005; 352 (10): 10111023.
Literature 8.1.3.6
1.
2.
3.
4.
5.
374
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Literature 8.1.4
1.
2.
3.
4.
5.
6.
7.
8.
9.
375
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
376
Goodnough LT, Despotis GJ, Merkel K, Monk TG. A randomized trial comparing acute
normovolemic hemodilution and preoperative autologous blood donation in total hip
arthroplasty. Transfusion 2000;40:1054-7.
Hobisch-Hagen P, Wirleitner B, Mair J, Luz G, Innerhofer P, Frischhut B, Ulmer H,
Schobersberger W. Consequences of acute normovolaemic haemodilution on haemostasis
during major orthopaedic surgery. Br J Anaesth. 1999 Apr;82(4):503-9.
Haynes SL, Torella F, Wong JC, Dalrymple K, James M, McCollum CN. Economic evaluation
of a randomized clinical trial of haemodilution with cell salvage in aortic surgery. Br J Surg.
2002 jun;89(6):731-6.
Hohn L, Schweizer A, Licker M, Morel DR. Absence of beneficial effect of acute
normovolemic hemodilution combined with aprotinin on allogeneic blood transfusion
requirements in cardiac surgery Anesthesiology 2002;96:276-282
Ickx BE, Bepperling F, Melot C, Schulman C, Van der Linden PJ. Plasma substitution effects
of a new hydroxyethyl starch HES 130/0.4 compared with HES 200/0.5 during and after
extended acute normovolaemic haemodilution. Br J Anaesth. 2003 Aug;91(2):196-202.
Jacob M, Bruegger D, Conzen P, Becker BF, Finsterer U, Rehm M. Development and
validation of a mathematical algorithm for quantifying preoperative blood volume by means of
the decrease in hematocrit resulting from acute normovolemic hemodilution. Transfusion.
2005 Apr;45(4):562-71.
Jalali A, Naseri MH, Chalian M, Dolatabadi HL.Acute normovolaemic haemodilution with
crystalloids in coronary artery bypass graft surgery: a preliminary survey of haemostatic
markers. Acta Cardiol. 2008 Jun;63(3):335-9.
Jamnicki M, Kocian R, van der Linden P, Zaugg M, Spahn DR. Acute normovolemic
hemodilution: physiology, limitations, and clinical use J Cardiothorac Vasc Anesth
2003;17:747-754
Jarnagin WR, Gonen M, Maithel SK, Fong Y, D'Angelica MI, Dematteo RP, Grant F, Wuest D,
Kundu K, Blumgart LH, Fischer M. A prospective randomized trial of acute normovolemic
hemodilution compared to standard intraoperative management in patients undergoing major
hepatic resection. Ann Surg. 2008 Sep;248(3):360-9.
Levi M, Jonge E. Clinical relevance of the effects of plasma expanders on coagulation.Semin
Thromb Hemost. 2007 Nov;33(8):810-5.
Licker M, Ellenberger C, Murith N, Tassaux D, Sierra J, Diaper J, Morel DR. Cardiovascular
response to acute normovolaemic haemodilution in patients with severe aortic stenosis:
assessment with transoesophageal echocardiography. Anaesthesia. 2004 Dec;59(12):11707.
Licker M, Sierra J, Tassaux D, Diaper J. Continuous haemodynamic monitoring using
transoesophageal Doppler during acute normovolaemic haemodilution in patients with
coronary artery disease. Anaesthesia. 2004 Feb;59(2):108-15.
Licker M, Ellenberger C, Sierra J, Kalangos A, Diaper J and Morel D. Cardioprotective effects
of acute normovolemic hemodilution in patients undergoing coronary artery bypass surgery.
Chest 2005; 128: 838-47.
Licker M, Sierra J, Kalangos A, Panos A, Diaper J and Ellenberger C. Cardioprotective effects
of acute normovolemic hemodilution in patients with severe aortic stenosis undergoing valve
replacement. Transfusion 2007; 47: 341-50.
Matot I,Scheinin O,Jurim O, et al. Effectiveness of AHHN to minimize allogenic blood
transfusion in major liver resections. Anesthesiology 2002; 97:794-800
McGill N, O'Shaughnessy D, Pickering R, Herbertson M, Gill R. Mechanical methods of
reducing blood transfusion in cardiac surgery: randomized controlled trial. BMJ. 2002 Jun
1;324(7349):1299. Erratum in: BMJ 2002 Jul 20;325(7356):142.
Monk TG, Goodnough LT, Brecher ME, Colberg JW, Andriole GL, Catalona WJ. A
prospective randomized comparison of three blood conservation strategies for radical
prostatectomy Anesthesiology 1999;91:24-33.
Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of
Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice
Guideline* Ann Thorac Surg 2007;83:S27-S86.
28.
29.
30.
31.
32.
33.
34.
35.
36.
Ramnath AN, Naber HR, de Boer A, Leusink JA. No benefit of intraoperative whole blood
sequestration and autotransfusion during coronary artery bypass grafting: results of a
randomized clinical trial J Thorac Cardiovasc Surg 2003;125:1432-1437.
Reents W, Babin-Ebell J, Misoph MR, Schwarzkopf A, Elert O. Influence of different
autotransfusion devices on the quality of salvaged blood Ann Thorac Surg 1999;68:58-62.
Rehm M, Haller M, Orth V, Kreimeier U, Jacob M, Dressel H, Mayer S, Brechtelsbauer H,
Finsterer U. Changes in blood volume and hematocrit during acute preoperative volume
loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy.
Anesthesiology. 2001 Oct;95(4):849-56.
Saricaoglu F, Akinci SB, Celiker V, Aypar U. The effect of acute normovolemic hemodilution
and acute hypervolemic hemodilution on coagulation and allogeneic transfusion. Saudi Med
J. 2005 May;26(5):792-8.
Singbartl K, Schleinzer W, Singbartl G. Hypervolemic hemodilution: an alternative to acute
normovolemic hemodilution? A mathematical analysis. J Surg Res. 1999 Oct;86(2):206-12.
Erratum in: J Surg Res 2000 Feb;88(2):215.
Suttner SW, Piper SN, Lang K, Httner I, Kumle B, Boldt J. Cerebral effects and blood
sparing efficiency of sodium nitroprusside-induced hypotension alone and in combination with
acute normovolaemic haemodilution. Br J Anaesth. 2001 Nov;87(5):699-705.
Weiskopf R, Feiner J, Hopf HW, Viele M, Watson J, Kramer JH, Ho R, Toy P: Oxygen
reverses deficits of cognitive function and memory and increased heart rate induced by acute
severe isovolemic anemia. A nesthesiology 2002; 96: 871-7.
Wolowczyk L, Nevin M, Day A, Smith FC, Baird RN, Lamont PM. The effect of acute
normovolaemic haemodilution on the inflammatory response and clinical outcome in
abdominal aortic aneurysm repair--results of a pilot trial. Eur J Vasc Endovasc Surg. 2005
Jul;30(1):12-9.
Zetterstrom H, Wiklund L. A new nomogram facilitating adequate haemodilution. Acta
Anaesth Scand 1985;(Suppl 80):29-71.
Literature 8.2.1
1.
2.
3.
4.
5.
6.
7.
8.
Aksoy MC, Tokgozoglu AM. Erythropoietin for autologous blood donation in total hip
arthroplasty patients. Arch Orthop Trauma Surg 2001;121:162-5.
Bouchard D, MD;* Bertrand Marcheix, MD;* Sfoug Al-Shamary, MD;* Frdric Vanden
Eynden, MD;* Philippe Demers, MD;* Danielle. Preoperative autologous blood donation
reduces the need for allogeneic blood products: a prospective randomized study. J can chir
2008:51 (6): 422-427.
Bovy C, Baudoux E, Salmon JP, Beguin Y. Increased iron absorption during autologous blood
donation supported by recombinant human erythropoietin therapy. Transfusion. 2006
Sep;46(9):1616-23.
Carless P, Moxey A, O'Connell D, Henry D. Autologous transfusion techniques: a systematic
review of their efficacy. Transfus Med. 2004 Apr;14(2):123-44.
Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C. Cost-effectiveness of cell
salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a
systematic review and economic model. Health Technol Assess. 2006 Nov;10(44):iii-iv, ix-x,
1-210.
Dietrich W, Thuermel K, Heyde S, Busley R, Berger K. Autologous blood donation in cardiac
surgery: reduction of allogeneic blood transfusion and cost-effectiveness. J Cardiothorac
Vasc Anesth. 2005 Oct;19(5):589-96.
Forgie MA, Wells PS, Laupacis A, Fergusson D. Preoperative autologous donation decreases
allogeneic transfusion but increases exposure to all red blood cell transfusion: results of a
meta-analysis. International Study of Perioperative Transfusion (ISPOT) Investigators. Arch
Intern Med. 1998 Mar 23;158(6):610-6.
Freedman J, Luke K, Escobar M, Vernich L, Chiavetta JA. Experience of a network of
transfusion coordinators for blood conservation (Ontario Transfusion Coordinators [ONTraC]).
Transfusion. 2008 Feb;48(2):237-50.
377
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Goodnough LT, Despotis GJ, Merkel K, Monk TG. A randomized trial comparing acute
normovolemic hemodilution and preoperative autologous blood donation in total hip
arthroplasty.Transfusion. 2000 Sep;40(9):1054-7.
Heiss MM, Fasol-Merten K, Allgayer H, Strhlein MA, Tarabichi A, Wallner S, Eissner HI,
Jauch KW, Schildberg FW. Influence of autologous blood transfusion on natural killer and
lymphokine-activated killer cell activities in cancer surgery. Vox Sang. 1997;73(4):237-45.
Henry DA, Carless PA, Moxey AE, Oonnell D, Forgey MA, Wells PS, Fergusson DA. Preoperative autologous donation for minimising perioperative allogenic bloodtransfusions
(Review) The Cochrane Library CD003602.:1-30, laatste update 2004.
Hyllner M, Avall A, Swolin B, Bengtson JP, Bengtsson A. Autologous blood transfusion in
radical hysterectomy with and without erythropoietin therapy. Obstet Gynecol. 2002 May;99(5
Pt 1):757-62.
Hyllner M, Avall A, Bengtson JP, Bengtsson A. IL-6 and IL-8 response to erythropoietin
therapy in radical hysterectomy. Acta Anaesthesiol Scand. 2005 Jan;49(1):47-51.
Innerhofer P, Klingler A, Klimmer C, Fries D, Nussbaumer W. Risk for postoperative infection
after transfusion of white blood cell-filtered allogeneic or autologous blood components in
orthopedic patients undergoing primary arthroplasty. Transfusion. 2005 Jan;45(1):103-10.
Regis D, Corallo F, Franchini M, Rosa R, Ricci M, Bartolozzi P. Preoperative autologous
blood donation in primary total knee arthroplasty: critical review of current indications. Chir
Organi Mov. 2008 Jan;91(1):41-4.
Rubens FD, Fergusson D, Wells PS, Huang M, McGowan JL, Laupacis A. Platelet-rich
plasmapheresis in cardiac surgery: a meta-analysis of the effect on transfusion requirements.
J Thorac Cardiovasc Surg 1998;116:641-7.
Shulman G, Solanski DR, Hadjipavlou A. Augmented autologous transfusion in major
reconstructive spine surgery. J Clin Apheresis 1998;13:62-8.
Singbartl G. Preoperative autologous blood donation - part I. Only two clinical parameters
determine efficacy of the autologous predeposit. Minerva Anestesiol. 2007 Mar;73(3):143-51
Singbartl G, Malgorzata S, Quoss A. Preoperative autologous blood donation - part II.
Adapting the predeposit concept to the physiological basics of erythropoiesis improves its
efficacy. Minerva Anestesiol. 2007 Mar;73(3):153-60.
Torella F, Haynes SL, Lardi A, O'Dwyer ST, McCollum CN. Unchanging attitudes to
autologous transfusion in the UK. Transfus Med. 2001 Feb;11(1):15-9.
Literature 8.2.2
1.
2.
3.
4.
5.
6.
7.
378
AABB. Guidelines to proposed standards for perioperative collection and transfusion. 1st
edition. AABB Association Bulletin 1997.
Abuzakuk T, V Senthil Kumar, Y Shenava, C Bulstrode, J A Skinner, S R Cannon, T W
Briggs. Autotransfusion drains in total knee replacement. Are they alternatives to homologous
transfusion? International orthopaedics. 2007; 31(2):235-9.
Altinel L, Kaya E, Kose KC, Fidan F, Ergan V, Fidan H. Effect of shed blood retransfusion on
pulmonary perfusion after total knee arthroplasty: a prospective controlled study. Int Orthop.
2007 Dec;31(6):837-44.
Amin A, Watson A, Mangwani J, Nawabi D, Ahluwalia R, Loeffler M. A prospective
randomised controlled trial of autologous retransfusion in total knee replacement. J Bone
Joint Surg Br. 2008 Apr;90(4):451-4.
Boodhwani M, Nathan HJ, Mesana TG, Rubens FD; Cardiotomy Investigators. Effects of
shed mediastinal blood on cardiovascular and pulmonary function: a randomized, doubleblind study. Ann Thorac Surg. 2008 Oct;86(4):1167-73.
Bowley DM, Barker P, Boffard KD. Intraoperative blood salvage in penetrating abdominal
trauma: a randomised, controlled trial. World J Surg. 2006 Jun;30(6):1074-80.
British. Guidelines for the clinical use of blood cell separators. Prepared by a joint working
party of the transfusion and clinical haematology task forces of the British committee for
standards in haematology. Clin Lab Haem 1998;20:265-78.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Carless PA, Henry DA, Moxey AJ, O'Connell DL, Fergusson DA. Cell salvage for minimising
perioperative allogeneic blood transfusion. The Cochrane Database of Systematic Reviews
2006, Issue 4. Art. No.: CD001888. DOI: 10.1002/14651858.CD001888.pub2.
Carrier M, Denault A, Lavoie J, Perrault LP. Randomized controlled trial of pericardial blood
processing with a cell-saving device on neurologic markers in elderly patients undergoing
coronary artery bypass graft surgery. Ann Thorac Surg. 2006 Jul;82(1):51-5.
Dalen T, Engstrom KG. Microrheology of filtered autotransfusion drain blood with and without
leukocyte reduction. Clin Hemorheol Microcirc 1999;21:113-23.
Davis M, Sofer M, Gomez-Marin O, Bruck D, Soloway MS.The use of cell salvage during
radical retropubic prostatectomy: does it influence cancer recurrence? BJU Int. 2003
Apr;91(6):474-6.
Djaiani G, Fedorko L, Borger MA, Green R, Carroll J, Marcon M, Karski J. Continuous-flow
cell saver reduces cognitive decline in elderly patients after coronary bypass surgery.
Circulation. 2007 Oct 23;116(17):1888-95.
Faught C, Wells P, Fergussion D, Laupacis A. Adverse effects of methods for minimizing
perioperative allogeneic transfusion: a critical review of the literature. Transfus Med Rev
1998;12:206-25.
Ferrari VA e.a. Perioperative blood transfusion and blood conservation in cardiac surgery: the
society of thoracic surgeons and the society of cardiovascular anesthesiologists clinical
practice guideline. Ann Thorac Surg 2007; 83: S27-86.
Ford BS, Sharma S, Rezaishiraz H, Huben RS, Mohler JL. Effect of perioperative blood
transfusion on prostate cancer recurrence. Urol Oncol. 2008 Jul-Aug;26(4):364-7. Epub 2007
Nov 7.
Gallina A, Briganti A, Chun FK, Walz J, Hutterer GC, Erbersdobler A, Eichelberg C, Schlomm
T, Ahyai SA, Perrotte P, Saad F, Montorsi F, Huland H, Graefen M, Karakiewicz PI.Effect of
autologous blood transfusion on the rate of biochemical recurrence after radical
prostatectomy. BJU Int. 2007 Dec;100(6):1249-53. Epub 2007 Sep 10.
Gharehbaghian A, Haque KM, Truman C, Evans R, Morse R, Newman J, Bannister G,
Rogers C, Bradley BA. Effect of autologous salvaged blood on postoperative natural killer cell
precursor frequency. Lancet. 2004 Mar 27;363(9414):1025-30.
Handel M, Boluki D, Loibl O, Schaumburger J, Kalteis T, Matussek J, Grifka J. Postoperative
autologous retransfusion of collected shed blood after total knee arthroplasty with the cell
saver. Z Orthop Ihre Grenzgeb. 2006 Jan-Feb;144(1):97-101.
Hansen E, Bechmann V, Altmeppen J. Intraoperative blood salvage in cancer surgery: safe
and effective? Transfus Apher Sci. 2002 Oct;27(2):153-7.
Hansen E, Bechmann V, Altmeppen J, Wille J, Roth G. Quality assurance in blood salvage
and variables affecting quality. Anasthesiol Intensivmed Notfallmed Schmerzther. 2004
Sep;39(9):569-75.
Hansen E, Pawlik M, Altmeppen J, Bechmann V. Autologous transfusion -- from euphoria to
reason: clinical practice based on scientific knowledge (Part II). Intraoperative blood salvage
with blood irradiation -- from an anaesthesiological point of view. Anasthesiol Intensivmed
Notfallmed Schmerzther. 2004 Nov;39(11):676-82.
Hansen E. Failed evidence of tumour cell removal from salvaged blood after leucocyte
depletion. Transfus Med. 2006 Jun;16(3):213-4; author reply 215-6.
Hendrych J. Use of post-operative drainage and auto-transfusion sets in total knee
arthroplasty. Acta Chir Orthop Traumatol Cech. 2006;73(1):34-8.
Horstmann WG, Slappendel R, Hellemondt van GG, Castelein RM, Verheyne CCPM. Safety
of retransfusion of filtered shed blood in 1819 patients after total hip or knee arthroplasty.
TATM 2009; 10: 174-81.
Het C, Salmi LR, Fergussion D, Koopman-van Gemert AWMM, Rubens F, Laupacis A,
ISPOT investigators. A meta-analysis of the effectiveness of cell salvage to minimize
perioperative allogeneic blood transfusion in cardiac and orthopedic surgery. Anesth Analg
1999;89:861-9.
379
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
380
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
not influence haemodynamic stability following coronary artery bypass grafting. Thorac
Cardiovasc Surg. 2007 Mar;55(2):68-72.
Selo-Ojeme DO, Feyi-Waboso PA. Salvage autotransfusion versus homologous blood
transfusion for ruptured ectopic pregnancy. Int J Gynaecol Obstet. 2007 Feb;96(2):108-11.
Epub 2007 Jan 19.
Sinardi D, Marino A, Chillemi S, Irrera M, Labruto G, Mondello E. Composition of the blood
sampled from surgical drainage after joint arthroplasty: quality of return. Transfusion. 2005
Feb;45(2):202-7.
Sirvinskas E, Veikutiene A, Benetis R, Grybauskas P, Andrejaitiene J, Veikutis V, Surkus J.
Influence of early re-infusion of autologous shed mediastinal blood on clinical outcome after
cardiac surgery. Perfusion. 2007 Sep;22(5):345-52.
So-Osman C, Nelissen RG, Eikenboom HC, Brand A. Efficacy, safety and user-friendliness
of two devices for postoperative autologous shed red blood cell re-infusion in elective
orthopaedic surgery patients: A randomized pilot study. Transfus Med. 2006 Oct;16(5):321-8.
Smith LK, Williams DH, Langkamer VG. Post-operative blood salvage with autologous
retransfusion in primary total hip replacement. J Bone Joint Surg Br. 2007 Aug;89(8):1092-7.
Stachura A, Krol R, Poplawski T e.a. Transfusion of intra-operative autologous whole blood:
influence on complement activation and interleukin formation. Vox Sanguinis 2010; 2; 239-46.
Stoffel JT, Topjian L, Libertino JA. Analysis of peripheral blood for prostate cells after
autologous transfusion given during radical prostatectomy. BJU Int. 2005 Aug;96(3):313-5.
Svenmarker S, Engstrm KG, Karlsson T, Jansson E, Lindholm R, Aberg T. Influence of
pericardial suction blood retransfusion on memory function and release of protein S100B.
Perfusion. 2004 Nov;19(6):337-43.
Takagi H, Sekino S, Kato T, Matsuno Y, Umemoto T. Intraoperative autotransfusion in
abdominal aortic aneurysm surgery: meta-analysis of randomized controlled trials. Arch Surg.
2007 Nov;142(11):1098-101.
Thomas D. Facilities for blood salvage (cell saver technique) must be available in every
obstetric theatre. Int J Obstet Anesth. 2005 Jan;14(1):48-50.
Thomas MJG. Infected and malignant fields are an absolute contraindication to intraoperative
cell salvage: fact or fiction? Transfus Med 1999;9:269-78.
Thorley PJ, Shaw A, Kent P, Ashley S, Parkin A, Kester RC. Dual tracer technique to
measure salvaged red cell survival following autotransfusion in aortic surgery. Nucl Med
Commun 1990;11:369-74.
Tripkovi B, Bukovi D, Saki K, Saki S, Bukovi N, Radakovi B. Quality of the blood
sampled from surgical drainage after total hip arthroplasty. Coll Antropol. 2008 Mar;32(1):15360.
Tsumara N, Yoshiya S, Chin T, Shiba R, Kohso K, Doita M. A prospective comparison of
clamping the drain or post-operative salvage of blood in reducing blood loss after total knee
arthroplasty. J Bone Joint Surg Br. 2006 Jan;88(1):49-53.
Tylman M, Bengtson JP, Avall A, Hyllner M, Bengtsson A. Release of interleukin-10 by
reinfusion of salvaged blood after knee arthroplasty.Intensive Care Med. 2001
Aug;27(8):1379-84.
Valbonesi M, Bruni R, Lercari G, Florio G, Carlier P, Morelli F. Autoapheresis and
intraoperative blood salvage in oncologic surgery. Transfus Sci 1999;21:129-39.
Vermeijden WJ, Hagenaars A, van Oeveren W, de Vries AJ. Do repeated runs of a cell saver
device increase the pro-inflammatory properties of washed blood? Eur J Cardiothorac Surg.
2008 Aug;34(2):350-3. Epub 2008 Jun 9.
de Vries AJ, Gu YJ, Post WJ, Vos P, Stokroos I, Lip H, van Oeveren W. Leucocyte depletion
during cardiac surgery: a comparison of different filtration strategies. Perfusion. 2003
Mar;18(1):31-8.
de Vries AJ, Vermeijden WJ, Gu YJ, Hagenaars JA, van Oeveren W. Clinical efficacy and
biocompatibility of three different leukocyte and fat removal filters during cardiac surgery. Artif
Organs. 2006 Jun;30(6):452-7.
381
65.
66.
67.
68.
69.
70.
71.
72.
73.
Waters JH, ShinJung Lee J, Klein E, OHara J, Zippe C and Potter PS . Preoperative
Autologous Donation Versus Cell Salvage in the Avoidance of Allogeneic Transfusion in
Patients Undergoing Radical Retropubic Prostatectomy. Anesth Analg 2004;98:53742.
Westerberg M, Gbel J, Bengtsson A, Sellgren J, Eidem O, Jeppsson A. Hemodynamic
effects of cardiotomy suction blood. J Thorac Cardiovasc Surg. 2006 Jun;131(6):1352-7.
Wiefferink A, Weerwind PW, van Heerde W, Teerenstra S, Noyez L, de Pauw BE, Brouwer
RM. Autotransfusion management during and after cardiopulmonary bypass alters fibrin
degradation and transfusion requirements. J Extra Corpor Technol. 2007 Jun;39(2):66-70.
Wixson RL, Kwaan HC, Spies SM, Zimmer AM. Reinfusion of postoperative wound drainage
in total joint arthroplasty: Red blood cell survival and coagulopathy risk. J Arthroplasty
1994;9:351-7.
Wollinsky KH, Oethinger M, Buchele M, Kluger P, Puhl W, Hinrich-Mehrkens H.
Autotransfusion bacterial contamination during hip arthroplasty and efficacy of cefurocime
prophylaxis: a randomized controlled study of 40 patients. Acta Orthop Scand 1997;68:22530.
Wong JCL, Torella F, Haynes SL, Dalrymple K, Mortimer AJ, McCollum CN, ATIS
Investigators. Autologous versus allogeneic transfusion in aortic surgery. Ann Surg
2002;235:145-51.
Wood GC, Kapoor A, Javed A. Autologous drains in arthroplasty a randomized control trial. J
Arthroplasty. 2008 Sep;23(6):808-13. Epub 2008 Feb 13.
Zacharopoulos A, Apostolopoulos A,Kyriakidis A . The effectiveness of reinfusion after total
knee replacement. A prospective randomised controlled study. International orthopaedics.
01/07/200707/2007; 31(3):303-8.
Allen 2007 (zie Tabel 8.14).
Literature 8.3
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
382
Aksoy MC, Tokgozoglu AM. Erythropoietin for autologous blood donation in total hip
arthroplasty patients. Arch Orthop Trauma Surg 2001;121:162-5.
Boldt J, Weber A, Mailer K, Papsdorf M, Schuster P. Acute normovolaemic haemodilution vs
controlled hypotension for reducing the use of allogeneic blood in patients undergoing radical
prostatectomy. Br J Anaesth 1999;82:170-4.
Borghi B, Ganelli G, Celleno D, Rizzoli study group on orthopaedic anesthesia.
Autotransfusion with predeposithaemodilution and perioperative blood salvage: 20 years of
experience. Int J Artif Organs 1999;22:230-4.
Gombotz H, Gries M, Sipurzynski S, Fruhwald S, Rehak P. Preoperative treatment with
recombinant human erythropoietin or predeposit of autologous blood in women undergoing
primary hip replacement. Acta Anaesthesiol Scand 2000;44:737-42.
Goodnough LT, Despotis GJ, Merkel K, Monk TG. A randomized trial comparing acute
normovolemic hemodilution and preoperative autologous blood donation in total hip
arthroplasty. Transfusion 2000;40:1054-7.
Goodnough LT, Monk TG, Despotis GJ, Merkel K. A randomized trial of acute normovolemic
hemodilution compared to preoperative autologous blood donation in total knee arthroplasty.
Vox Sang 1999;77:11-6.
Jagt C van der, Trip D, Dekker M, Gassmann-Mayer C, Vercammen E, Hayes-Licitra S.
Effectiviteit en veiligheid van epotine alfa bij grote electieve orthopedische operaties: een
gerandomiseerde, placebogecontroleerde doseringsstudie. Ned Tijdschr Orthopaedie
2000;8:12-20.
Koopman-van Gemert AWMM. How to save blood: alternative approaches in Anaesthesiology
and Surgery. In Alternative Approaches to Human Blood Resources in Clinical Pratice 1997.
Editor C.Th. Smit Sibinga, P.C. Das, J.C. Fratantoni.. pag 161-167.
Monk TG, Goodnough LT, Brecher ME, Colberg JW, Andriole GL, Catalona WJ. A
prospective randomized comparison of three blood conservation strategies for radical
prostatectomy. Anesthesiology 1999;91:24-33.
Oishi CS, DLima DD, Morris BA, Hardwick ME, Berkowitz SD, Colwell CW Jr. Hemodilution
with other blood reinfusion techniques in total hip arthroplasty. Clin Orthop 1997;339:132-9.
11.
12.
12.
13.
14.
15.
16.
Price TH, Goodnough LT, Vogler WR, Sacher RA, Hellman RM, Johnston MF, et al.
Improving the efficacy of peroperative autologous blood donation in patients with low
hematocrit: a randomized, double-blind, comtrolled trial of recombinant human erythropoietin.
Am J Med 1996;101(2A):S22-7.
Shapira Y, Vurman G, Artru AA, Ousyscher IE, Lam AM, Kollender Y, et al. Combined
hemodilution and hypotension monitored with jugular bulb oxygen saturation, EEG and ECG
decreases transfusion volume and length of ICU stay for major orthopedic surgery. J Clin
Anesth 1997;9:643-9.
Stover EP, Siegel LC, Hood PA, ORiordan GE, McKenna TR. Platelet-rich plasma
sequestration, with therapeutic platelet yields, reduces allogeneic transfusion in complex
cardiac surgery. Anesth Analg 2000;90:509-16.
Suttner SW, Piper SN, Lang K, Huttner I, Kumie B, Boldt J. Cerebral effects and blood
sparing efficiency of sodium nitroprusside for controlled hypotension during spinal surgery in
adolescents. Anesth Analg 1997;84:1239-44.
Tempe D, Bajwa R, Cooper A, Nag B, Tomar AS, Khanna SK, et al. Blood conservation in
small adults undergoing valve surgery. J Cardiothorac Vasc Anesth 1996;10:502-6.
Weber EWG, Slappendel R, Schaaf DB van der, Oosting JD. Halvering van de toediening van
packed cells bij geprotocolleeerde indicatiestelling. Ned Tijdschr Geneeskd 2000;144:10-2.
Xenakis TA, Malizos KN, Dailiana Z, Koukoubis T, Zervou E, Golegou C, et al. Blood salvage
after total hip and total knee arthroplasty. Acta Orthop Scand 1997;68(Suppl 275):135-8.
383
Introduction
Paragraph 4 contains general information about the use of quality indicators. In addition,
suggestions are made for possible indicators, which could provide insight into the quality of
every step. The guideline working group is of the opinion that every hospital should
determine for itself how the blood transfusion process should be monitored, depending on
the local conditions. However, comparison is made possible if hospitals (also) use the same
indicators. The guideline working group is convinced that this will promote transparency and
contribute to improving the quality, including the indication setting.
9.4
Quality indicators
9.4.1 Introduction
Monitoring the quality of blood transfusions is essential. The aim of this monitoring is not so
much providing external accountability, but more the systematic search for possibilities to
improve the system. Indicators can play a role in this. Indicators are measureable elements
of the care provided, which provide a measure of the quality of the care provided. Indicators
can be divided into 3 categories:
- Structural indicators
Structural indicators provide information about the (organisational) boundary conditions
within which the care is provided. An example of a structural indicator is the presence or
absence of a blood transfusion committee.
Process indicators
Process indicators provide information about the actions that are performed within a care
process to provide quality. The characteristic of process indicators is that they can be
influenced directly: they measure how (often) something is done. An example of a process
indicator is: The percentage of erythrocyte transfusions with a pre-transfusion Hb > 6.0
mmol/L within 24 hours before transfusion.
Outcome indicators
Outcome indicators provide information about the outcome of care processes measured at a
patient level. Outcome indicators depend on many factors and are therefore often hard to
trace back to direct patient care. An example of an outcome indicator is: the percentage of
patients with a transfusion reaction of severity grade 2 or higher.
Outcome indicators best approach the aim of indicators (measuring the quality of care).
Structural and process indicators can provide further insight into possible conditions or
processes that could improve care.
384
A number of the indicators mentioned in this chapter can only be implemented if both the
hospital and the transfusion laboratory have adequate IT services.and/or if adequate
agreements are made about the coding of patient categories in diagnosis treatment
combinations (DBC) or ICD-10 codes. Unfortunately, this is not yet the case in every
hospital.
In addition to generating directing information, one must also ensure that action is taken
based on this information to improve the quality of care. There must be support among the
employees in the primary process as well as management to facilitate the setting up of data
collection, the actual implementation and the monitoring of improvement actions.
9.4.2 Why internal indicators?
An indicator has a type of signalling function: it is not a direct measure of quality, but points
to a certain aspect of the functioning and can be a cause for further investigation. It concerns
the core of quality care: the actual measurement of aspects related to the quality of care and
based on this measurement the implementation of improvements aimed at targeted
improvement of the quality of care.
Indicators can give care providers insight into the results of their own care process and
assist in the internal guidance and improvement of this process. Indicators with this goal are
called internal indicators. On the other hand, indicators can serve to provide accountability of
the quality of care, for example to government authorities, health care insurers or patients.
These are called external indicators, because they serve an external goal. Indicators can
also be used to compare the performance of care providers or institutions (benchmarking).
These are then termed internal or external indicators, depending on the goal for which and
by whom they are used.
The indicators formulated for the current Blood Transfusion Guideline were developed by
and for care providers and are aimed at improving the quality of the transfusion process.
Therefore, these are internal indicators.
9.4.3 How were the indicators created?
The indicators that are to be developed should provide insight into the quality of care. This
can include various quality domains, such as: efficacy, safety, efficiency or timeliness.
The Blood transfusion internal indicators were generated by following the steps in the
Indicator Development Manual. An extensive description of these steps is provided in the
Indicator Development Manual, available on the website of the CBO (www.cbo.nl). This
manual is derived from the AIRE instrument (Appraisal of Indicators, Research and
Evaluation). The AIRE instrument is a methodological instrument that serves as an
evaluation and testing framework for indicators. All relevant elements from the AIRE
instrument were applied in the drafting of the indicators.
The blood transfusion guideline working group was asked to form a sub working group
consisting of a small number of individuals who could focus on the development of the
internal indicators during the last phase of the revision of the guideline (the phase of
385
discussing and approving the recommendations). Eventually, a sub working group of three
working group members was formed who supported by the CBO worked on the
development of the internal indicators.
Based on the draft Blood Transfusion Guideline, the sub working group created an inventory
of potential indicators related to the aspect of quality of care surrounding blood transfusion
practices. A search was also performed for international indicators that have already been
developed. These potential indicators were submitted to the entire guideline working group
and the working group members were asked to comment on, to prioritise and to indicate
which aspects of the care with a (supposed) relationship to the quality of care they
deemed important. These aspects were processed for possible translation into an indicator.
This resulted in a list of indicator topics, which were discussed in various meetings of the
sub working group and via e-mail. Next, the indicators were prioritised. This prioritisation was
performed based on methodological requirements (think of validity, discerning ability and
reliability), but arguments such as recordability and the extent to which the indicators meet
the specific goals set by the working group during the revision of the guideline also played a
role. The argumentation for scrapping potential indicators was documented.
The selected indicators were worked out in fact sheets (see paragraph 9.4.5 Elaboration of
indicators in fact sheets). The characteristics of the indicator are described in a fact sheet,
such as the type of indicator (process, structural, outcome) and the quality domain to which
the indicator is related. The concept fact sheets were discussed by the core group involved
in the guideline and submitted to the guideline working group for comments. The indicators
were then submitted to the scientific and professional organisations together with the
guideline for consultation. A pilot was also performed by TRIP, in which the indicators were
tested to check that they are unambiguous and feasible. Once the results from the pilot and
the comments from the consultation round were processed, the scientific and professional
organisations (see the introduction to this guideline) authorised the resulting internal
indicators.
9.4.4 Use and implementation of indicators
A verdict on the quality of care during blood transfusions can only be made if one can
measure whether the quality criteria as described in the guideline have been met. The
indicator sub working group deems it possible to survey the quality of care as an individual
care provider using the indicators related to the Blood Transfusion Guideline, as developed
by the indicator sub working group. For the selected and detailed indicators, the indicator
sub working group expects that the detailed indicators are valid (expert validation), that the
indicators can be measured reliably and that the indicators will provide (more or less) the
same results under constant conditions. The indicator sub working group is also of the
opinion that the indicators discriminate sufficiently, as there appears to be enough variation
in practice. Finally, the working group does not think it necessary to monitor for differences in
demographic and socio-economic composition or health status of patient groups.
Ultimately, the results of the indicators can also provide an incentive to modify or update the
Blood Transfusion Guideline.
386
The actual implementation and measurement of these indicators falls beyond the
responsibility of the indicator sub working group.
9.4.5 Elaboration of indicators in fact sheets
The fact sheets of the indicators are presented in this paragraph.
Indicator 1. Blood Transfusion Committee
Relationship to
quality
The Care Facility Quality Law demands reliable care at all times for all
patients.
Efficacy and safety play an important role in the optimisation of the
quality of blood transfusions.
The quality requirements that blood transfusions should meet in order to
be safe and effective have been formulated in the current Blood
Transfusion Guideline. The Board of Directors is responsible for
ensuring that the medical staff of the institution evaluates the quality of
the blood transfusions performed. A locally appointed blood transfusion
committee is charged with translating the national guidelines into a local
protocol and with evaluating the quality of the blood transfusion chain
and guaranteeing the quality. The data about safety and efficacy of
blood transfusions collected in evaluations can be discussed by this
blood transfusion committee, including the causistics. This can result in
rapid amendment of the local protocol. This should result in the
principles as stated in the guideline actually being implemented in
practice.
In accordance with the Care Facility Quality Law, every hospital must
have a blood transfusion committee. It is recommended that this blood
transfusion committee meets at least 4 times per year.
Operationalisation
Definitions
Inclusion
and
exclusion criteria
Type of indicator
Quality domain
387
The indicator relates to the care facility as a whole and to all disciplines involved in blood
transfusions. The following disciplines and institutions should preferably be included in a
blood transfusion committee: all disciplines that use blood, blood transfusion laboratory,
haemovigilance official and haemovigilance
employee, nurses and CCS (Clinical
Consultative Service) doctor of Sanquin Blood Supply.
This means that the most important disciplines involved in blood transfusions should be
represented in this committee. The working group is of the opinion that in each hospital, a
blood transfusion committee is charged with protocol development, testing of the
implementation of the agreements in the policy, evaluation of blood transfusions and the
drafting of quality standards for a training plan for all involved employees in the hospital and
the testing of this plan. The Board of Directors, by law, sets the criteria and monitors the
committee.
Background and variation in quality of care
No similar research has been performed from which one could conclude that an active blood
transfusion committee improves the quality of blood transfusions. However, in order to
achieve adequate implementation and regular evaluation of the guideline in every care
facility, a central blood transfusion committee appears to be an obvious choice.
The institution (Board of Directors) is responsible for ensuring that the medical staff of the
institution evaluates the quality of the blood transfusions performed. The aim should be to
guarantee the quality of all blood transfusions performed in the Netherlands by a local
committee.
Possibilities for improvement
If no blood transfusion committee exists (indicator 1A), one can be appointed. If a blood
transfusion committee does exist, but they meet less than 4 times per year, benchmarking of
indicator 1B can contribute to making the committee more active. The working group expects
that most hospitals will have a blood transfusion committee, but that this committee
convenes less than 4 times per year.
Minimal bias / description of relevant case mix
No meaningful case mix problems are expected.
Literature
1.
2.
388
Operationalisation
Definitions
Inclusion
and
exclusion criteria
A.
Type of indicator
Quality domain
Structural indicator
B.
Structural indicator
Efficacy, safety and efficiency
389
the quality of this care. Therefore, the working group expects a positive correlation between
the activities of a haemovigilance employee in an institution and a positive/good score on the
other indicators
The organisational link to which the indicator is related
The indicator is related to all departments and other business sections of care facilities that
are involved in the blood transfusion chain in the care facility.
Background and variation in quality of care
The Care Facility Quality Law demands systematic monitoring, control and improvement of
the quality of care. In order to achieve this, the entire transfusion chain must be documented
from donor to patient. (Sanquin) Blood Supply, hospital laboratories and clinical departments
each have their own responsibilities. The processes should be synchronised with each other.
There is a legal obligation to report all (serious) side effects of transfusion. The working
group is of the opinion that an adequate hospital haemovigilance system and the
appointment of a haemovigilance employee are important factors that can contribute to this
systematic monitoring, control and improvement of the quality of (Dutch) blood transfusion
practice.
Possibilities for improvement
The working group expects that in the Netherlands not every hospital will have a
haemovigilance employee employed for at least 8 hours per week. It is also expected
that there will be opportunities for improvement of this point.
Minimal bias / description of relevant case mix
The indicator is a structural indicator that does not depend on the case mix. Finally, the
working group does not think it necessary to monitor for differences in demographic and
socio-economic composition or health status of patient groups.
390
Operationalisation
Not applicable
Definitions
Inclusion
and Not applicable
exclusion criteria
Structural indicator
Type of indicator
Efficacy, efficiency
Quality domain
391
1.
2.
The specification and use of Information Technology (IT) systems in Blood Transfusion
Practice British Committee for Standards in Haematology, Blood Transfusion Task Force.
2006 http://www.bcshguidelines.com/.
Guideline on the Administration of Blood Components British Committee for Standards in
Haematology 2009 http://www.bcshguidelines.com/.
Operationalisation
Definitions
Inclusion
and
exclusion criteria
Structural indicator
Type of indicator
Efficacy, safety and efficiency
Quality domain
392
identification checks of patient and blood components can contribute significantly in (Dutch)
blood transfusion practice to the monitoring, control and improvement of the quality of care.
Possibilities for improvement
The working group expects that very few (Dutch) hospitals will have implemented an
automated system for identification checks of patients and blood components prior to blood
transfusion, but that many hospitals will have plans to implement such a system in future. It
is also expected that there will be opportunities for improvement of this point.
Minimal bias / description of relevant case mix
The indicator is a structural indicator that does not depend on the case mix. Finally, the
working group does not think it necessary to monitor for differences in demographic and
socio-economic composition or health status of patient groups.
Indicator 5. Indication setting for erythrocyte transfusions
Relationship to
quality
Operationalisation
Numerator
Denominator
393
Definitions
Inclusion
and
exclusion criteria
Process indicator
Type of indicator
Safety, timeliness, efficiency
Quality domain
394
American College of Physicians. Practice strategies for elective red blood cell transfusion.
Ann Intern Med 1992;116:403-6.
British Committee for Standards in Haematology. Guidelines for the clinical use of red cell
transfusions. Br J Haematol 2001;113:24-31.
Consensus conference: perioperative red blood cell transfusion. JAMA 1988;260:2700-3.
4.
5.
6.
7.
8.
9.
10.
11.
Expert Working Group. Guidelines for red blood cell and plasma transfusions for adults and
children. Can Med Assoc J 1997;156 (Suppl 11):S1-25.
Goodnough LT. Transfusion triggers. Surgery. 2007;142: S67-70.
Hebert PC, Wells G, Blajchman MQ, Marshall J, Martin C, et al. A multicenter, randomized,
controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements
in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:
409-17.
Practice guidelines for blood component therapy: a report by the American Society of
Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996;84:73247.
Walsh TS, Garrioch M, Maciver C, Lee RJ, MacKirdy F, McClelland DB, et al. Red cell
requirements for intensive care units adhering to evidence-based transfusion guidelines.
Transfusion. 2004;44:1405-1411.
Gombotz et al. Transfusion 2007;47:1468-80.
Brunskill SJ, Hyde CJ, Stanworth SJ, Doree CJ, Roberts DJ, Murphy MF. Improving the
evidence base for transfusion medicine: the work of the UK systematic review initiative.
Transfus Med 2009 Apr;19(2):59-65.
Maki T. Optimizing blood usage through benchmarking. Transfusion 2007 Aug;47(2
Suppl):145S-8S.
Operationalisation
Numerator
Denominator
Definitions
Inclusion
and
exclusion criteria
Process indicator
Type of indicator
Safety, timeliness, efficiency
Quality domain
Blood Transfusion Guideline, 2011
395
2.
3.
4.
5.
6.
7.
8.
396
Indicator 7: Traceability
Relationship
quality
Operationalisation
Numerator
Denominator
Inclusion
and none
exclusion criteria
Process indicator
Type of indicator
Efficiency
Quality domain
The aim of the indicator
The aim of indicator 7 is to determine whether the EU requirements concerning traceability
of blood components have been met. The information obtained from this indicator shows
whether the institution meets the set legal requirements. Ideally, every institution should be
able to answer 100% to this question. However, it is expected that not all institutions can
meet this requirement. Indicator 7 must provide information about the efficiency of the
traceability in the hospital.
The organisational link to which the indicator is related
This indicator applies to the hospital-wide use of (short shelf-life) blood components.
Background and variation in quality of care
For the traceability of all short shelf-life blood components in the hospital, it is important to
implement a system that works well for the confirmation of administration of a unit.
Possibilities for improvement
The working group expects that the opportunities for improvement are great, because
compliance with the guideline on this point is not widespread in practice in (Dutch) hospitals.
Minimal bias / description of relevant case mix
This is a process indicator that does not depend strongly on the case mix. The working
group does not think it necessary to monitor for differences in demographic and socioeconomic composition or health status of patient groups.
397
Literature
1.
2.
3.
4.
5.
398